This application claims priority to International Patent Application No. PCT/IB2020/051683 filed Feb. 27, 2020, which claims priority to Great Britain Patent Application GB 1913991.4 filed Sep. 27, 2019 and Great Britain Patent Application GB 1902731.7 filed Feb. 28, 2019, the contents of each of which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to stabilised hypochlorous solutions and their medical and cosmetic uses. More particularly it relates to their use in the treatment of humans and animals by application to the skin, both external and internal surfaces, and more particularly, but not exclusively, to the treatment of wounds and the oral cavity. It also relates to its use in the tattoo industry and to applications as anti-viral targeting for example viruses as set out herein, including coronavirus.

BACKGROUND

The prior art discussed falls into two categories.

Generally, hypochlorous solutions are known to be effective anti-microbials. Indeed, as long ago as 1915, Alexis Carrel and Henry Dakin were championing its benefits.

However, a major problem with successful uptake is its poor shelf life because, in its natural state, hypochlorous has a half-life of 48 hours, unless stabilised.

WO2012123695 teaches a “stable” antimicrobial aqueous hypochlorous acid solution that retains its activity for at least three months and can be provided with high levels of hypochlorous acid (more than 500 ppm). The aqueous hypochlorous acid composition has low chloride ion concentrations (maximum chloride levels of 1:3 chloride to hydrochlorous acid) and a pH between 3.5 and 7.0.

The publication teaches the “stable compositions” (the activity of which in-fact varies with pH) may be used in a wide range of applications, the primary one exemplified being for sanitizing surfaces. It does however also teach its use in medicine to treat e.g. wounds, but no supporting evidence is provided, and no indication is given of the concentration of hypochlorous acid that may be required. Indeed, the general teaching is of a range of anywhere between 10 and 130,000 ppm, with the stability test data being with a solution containing 5000 ppm of “chlorine”, apparently hypochlorous. This solution is still an order of magnitude higher than that contemplated with the hypochlorous solutions of the present invention which retain their high hypochlorous level over time.

GB2521810, which reference is incorporated by reference, teaches a method and apparatus for producing a stable acidic chlorinated solution having a pH between 3.0 and 6.5, a stability such that at 6 weeks storage at 20° C. the pH remains in the same range, and the amount of chlorine lost is less than 10%. Again, the general teaching focuses on a total chlorine content of 5000 ppm and the Example with the lowest chlorine concentration exceeds 1000 ppm. It's states its use in disinfection and in the chlorination of water. The chlorine dissolves in water to produce hypochlorous acid, hydrogen ions and chloride ions and the hypochlorous dissociates to produce hydrogen ions and hypochlorite ions.

The medical uses of hypochlorous are known per se. Hypochlorous acid has been investigated as a possible wound care agent and as of early 2016 the U.S. Food and Drug Administration has approved products whose main active ingredient is hypochlorous acid for use in treating wounds and various infections in humans and pets.

The referenced publications are:

Wang L et al. “Hypochlorous acid as a potential wound care agent. Part I Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity”.J Burns and Wounds2007; April: 65-79. This document discloses stabilized HOCl in the form of a physiologically balanced solution in 0.9% saline, at a pH range of 3.5 to 4.0. Chlorine species distribution in solution is a function of pH. In aqueous solution, HOCl is the predominant species at the pH range of 3 to 6. At pH values less than 3.5, the solution exists as a mixture of chlorine in aqueous phase, chlorine gas, trichloride (Cl3—), and HOCl. At pH greater than 5.5, sodium hypochlorite (NaOCl) starts to form and becomes the predominant species in the alkaline pH. To maintain HOCl solution in a stable form, maximize its antimicrobial activities, and minimize undesirable side products, the pH must be maintained at 3.5 to 5.

Robson M C et al. “Hypochlorous acid as a potential wound care agent. Part II Stabilized hypochlorous acid: its role in decreasing tissue bacterial bioburden and overcoming the inhibition of infection on wound healing”.Journal of Burns and Wounds2007; April: 80-90. This document teaches stabilized hypochlorous acid (NVC-101) prepared by the addition of sodium hypochlorite to a solution of sodium chloride in sterile water followed by addition of a solution of hydrochloric acid and maintained at a pH between 3.5 and 5 has been demonstrated to have excellent in vitro antibacterial properties. Its potential limitation is the requirement to maintain its narrow pH range in the clinical wound environment.

Selkon, J B; et al. (2006). “Evaluation of hypochlorous acid washes in the treatment of venous leg ulcers”. J Wound Care. 2006 (15): 33-37. This document teaches the production of hypochlorous in situ, at a pH of 5.4 to 5.8.

A problem with the medical application of hypochlorous solutions, unlike general sanitation, is the need for consistency and accuracy of product with a shelf life of at least 3 months and preferably longer. It is also desirable for it to have a reasonable life once opened. Applicant has worked with solutions manufactured according to the process described in GB2521810 but rather they produce much lower concentrations of total chlorine by careful (stoichiometric) control of the reactants: water, hypochlorite salt (typically a sodium or calcium salt), and acid (typically phosphoric acid). This results in a relatively low total chlorine content (below 500 ppm) but very importantly a high, predominant, concentration of hypochlorous, and a ratio of hypochlorous to hypochlorite of greater than 3:1 and more preferably much higher which distinguishes it from prior art solutions. This high ratio of hypochlorous to hypochlorite, coupled with the relatively low total chlorine makes them particularly suitable for medical applications where the solution is applied to the skin or wounds of humans or animals. This coupled to higher pH's make it possible to use bottled hypochlorous solutions rather than seeking to produce hypochlorous in situ.

As described in GB2521810 the reaction utilises:i) a source of water having an electrical conductivity of no more than 500 μScm−1 at 20° C.;ii) a high (greater than 60% pure) purity hypochlorite salt, such as calcium hypochlorite (the sodium salt may also be used); andiii) an acid to adjust the pH to between 3.0 and 6.5.

The water is a “de-ionised water” with a minimal chlorine content and a defined conductivity.

Preferably the water has been subject to a reverse osmosis process and a “polishing” process using a mixed bed ion exchange resin wherein residual ions (such as chloride ions) are exchanged for H+and OH−ions.

It may additionally have been treated to kill microbes, using electromagnetic radiation, such as ultra-violet (UV) radiation and filtered through a filter, such as a 1 micron filter.

The hypochlorite salt may be calcium hypochlorite, with a purity level of at least 60% pure (by weight) and a low chloride content.

The, for example, calcium hypochlorite is mixed in the appropriate stoichiometric amount with the water to produce the desired concentration and the pH controlled with e.g. phosphoric acid, with the precipitate being removed by e.g. filtration.

Alternatively, the salt may be a high purity sodium hypochlorite.

Hydrochloric acid should not be used because it is a source of chloride ions which will negatively impact the stability of the final product.

These solutions of the invention, with a defined hypochlorous concentration (in ppm) and having a high ratio of hypochlorous to hypochlorite, have been demonstrated to have good shelf life and good efficacy overcoming many of the issues faced by hypochlorous products currently available which also contain relatively high hypochlorite levels.

Therapeutically this is very significant since the hypochlorous is much more efficacious and non-toxic whereas the hypochlorite is more than a log fold less efficacious and is toxic in nature.

The Applicant has further tested two preferred, low concentration, solutions in clinical settings and found them to be highly effective in promoting cell regeneration as well as acting as antimicrobials, including being highly effective against viruses including corona virus.

In the field of dentistry and oral hygiene the gold standard treatments comprise chlorohexidine gluconate. These mouthwashes can irritate ulcers and mucus membranes. Furthermore, they may cause staining, allergic reactions and do nothing to promote cell regeneration. Microbes can also become resistant to chlorhexidine.

Alternative antimicrobials used in medicine include isopropyl alcohol and povidone iodine.

They have also tested the product as a cosmetic, as a product for use in the tattoo industry with impressive results compared to the use of “green soap” the standard product used in the industry.

At first sight it may appear to the uninitiated that one hypochlorous solution will be much like another. However, as is apparent from observations made in prior art solutions Applicants ability to produce a stable hypochlorous solution with a high ratio of hypochlorous to hypochlorite (greater than 3:1) is a very significant industry development

Thus, for example US2017/0266227, FIG. 10, illustrates even the best “reagent grade” hypochlorous loses a third of its active hypochlorous in 12 weeks and will have halved (by extrapolation) in less than 18 weeks. Such compositions, as illustrated by for example, applicant's comparative example—see FIG. 4A, do not have the high hypochlorous: hypochlorite ratio that Applicants product has ensuring its superior efficacy.

Similarly, it will be noted that in WO2015/061632, page 2, paragraph 2, it is acknowledged that an aqueous HOCl solution at pH 4-6 in which the HOCl is the predominant active species is an effective topical disinfectant, However, the very next paragraph goes on to explain the difficulties and limitations in storage are a major problem. Indeed the specification uses terms such as “the remarkable difficulty of storing them” has led to the creation of machinery to generate such solutions in situ. Whilst the Examples are stated to produce specified concentrations of hypochlorous (100 and 500 ppm) of low chlorine content (less than 5 ppm) but of undefined hypochlorite. What is taught in the Examples is that various phosphates are added in the manufacture and US2017/0266227 teaches that surprisingly a phosphate buffer negatively impacts on the hypochlorous as illustrated inFIG.10therein

Other art identified with similar limitations include

JP2003052796 which is acidified with HCl and includes phosphoric acid

WO2019006217 which appears to be no more than a description of desire with no specific teaching of processes used to obtain the disclosed formulations which are silent on their content other than a hypochlorous content; and

JP2003/052796, which is acidified with HCl,

SUMMARY

In accordance with the present inventions there is provided a bottle or an otherwise contained stabilised hypochlorous solution comprising:hypochlorous acid (HOCl),hypochlorite (ClO−), andchlorine (Cl−),
which species combined provide a total chlorine concentration, characterised in that;the total chlorine concentration is at or below 300 ppm;the hypochlorous, measured by UV spectroscopy at 230 nm, is the predominant species;the hypochlorite, measured by UV spectroscopy at 290 nm, is present at significantly lower levels than that of the hypochlorous, such that ratio of hypochlorous acid to hypochlorite of greater than 3:1; andthe solution has a pH of between about 7 and 4 and has a shelf life of at least 3 months, at 22° C., such that the amount of hypochlorous present remains at above 50% of its starting concentration, and the pH remains above 3.5.

In a preferred embodiment the solution has a shelf life, at 22° C., of at least 6 months, more preferably at least 9 months through 12 months, 15 months, 18 months, 21 months to 24 months or more.

Most preferably, at each of these time intervals the amount of hypochlorous present remains at above 60% through 65%, 70%, 75%, 80%, 85% and 90%.

In addition to good shelf life (period of storage) it is important that the product has a once open life, at 22° C., of at least 2 weeks and preferably at least 4 weeks, such that the amount of hypochlorous present remains at above 80% of its concentration before opening.

For a solution with a chlorine content of about 250 ppm this can be 3 months, and for a product with a chlorine content of about 80 ppm this should be at least 4 weeks.

In the solutions of the invention the ratio of hypochlorous to hypochlorite remains Greater than 3:1, more preferably greater than, 4:1 through each of 5:1, 6:1, 7:1, 8:1 or more during storage.

Preferably the pH remains at above 5, more preferably above 4.5, through 4 to above at least 3.5.

Most preferably the ratio of hypochlorous to hypochlorite is greater than 3:1, more preferably still greater than 5:1, through 7.5:1 to greater than 9:1. The ratio is generally higher for the about 250 ppm product than the about 80 ppm product.

In a first, preferred, embodiment the contained stabilised hypochlorous solution has a total chlorine concentration of about 250 ppm+/−20% with a starting concentration of hypochlorous of between 120 and 160 ppm.

This embodiment has been demonstrated to be particularly effective in treating a number of medical conditions including wounds, particularly chronic wounds, such as, for example, ulcers, as well as burns, urticaria as well as in the treatment of acne, spots and pimples.

It has further proved effective in cosmetic applications and in tattoo care reducing redness, swelling and pain during tattooing, (enabling the artist to work longer on a subject) when applied before and during the tattooing procedure, as well as speeding healing times. It further improved colour retention.

It may also be used pre, during and post tattoo removal. The tattoo removal process may be a laser process or by micro-needling.

The hypochlorous solution of the invention has also been shown to be very effective against viruses including corona virus.

It has also been demonstrated to have a shelf life of up to 2 years and a once open life of up to 3 months, retaining its relative hypochlorous levels and a high ratio of hypochlorous to hypochlorite which contributes significantly to its medical activity.

In a second, preferred, embodiment, and one particularly suited for dental applications and oral hygiene there is provided a contained stabilised hypochlorous solution which has a total chlorine concentration of about 80 ppm+/−20% and the starting concentration of the hypochlorous is above 40 ppm and more preferably above 50 ppm to about 55 pppm.

In accordance with a second aspect of the present invention there is provided the contained stabilised hypochlorous solution of the first preferred embodiment for use in the treatment of a number of medical conditions including wounds, particularly chronic wounds, such as, for example ulcers, as well as burns, urticaria as well as in the treatment of acne, spots and pimples.

In accordance with a third aspect of the present invention there is provided the contained stabilised hypochlorous solution of the second preferred embodiment for use in the treatment of dental and/or oral hygiene diseases and conditions including, but not limited to implants, extractions, dental caries, periodontitis, lichen planus, implantitis, gingivitis, mucosal bleeding, ulcers, bad breath, gum health and excess plaque.

The solution used in this aspect typically takes the form of a mouthwash.

The “contained” solution is contained in a bottle or other suitable container. The container should be impervious to light and may comprise a measuring aid or spray delivery device in order to facilitate easy application.

In accordance with a fourth aspect of the present invention there is provided a method of treating a subject for a condition selected from treatment of wounds, burns, the oral cavity, urticaria or acne, spots or pimples, comprising administering a contained stabilised hypochlorous solution to the subject.

The solution may be administered directly or applied to, for example a dressing, bandage, gauze or the like.

In accordance with a fifth aspect of the present invention there is provided a stabilised hypochlorous solution of the first or second aspect of the invention for use in treating a viral respiratory infection.

In one embodiment the viral respiratory infection is a corona virus infection. More particularly it is caused by COVID-19.

In accordance with a sixth aspect of the present invention there is provided a method of treating a viral respiratory infection comprising applying a stabilised hypochlorous solution of the first or second aspect of the invention to a subject.

In a preferred embodiment the solution is applied to the skin externally.

In another embodiment it is applied internally. It may be delivered to the oral cavity as a spray or as a liquid or the lungs as a spray or nebuliser. It may also be delivered to the lungs nasally.

