Stable Antiviral Formulation

Abstract

Antiviral compositions are disclosed comprising a) p-menthane-3,8-diol (PMD), b) one or more solvents chosen from C1-C5 primary alcohols and C3-C5 secondary alcohols as defined therein or combinations

Description

FIELD OF THE INVENTION The present invention relates to an antiviral formulation; and more specifically to stable 5 formulations comprising p-Menthane-3,8-diol (PMD). BACKGROUND TO THE INVENTION The insect-repellent effect of essential oils from the lemon eucalyptus tree (Corymbia citriodora, formerly known as Eucalyptus citriodora) has been known for some time. The 10 active ingredient of these oils is PMD (p-Menthane-3,8-diol; also known as menthoglycol, or 2-(2-Hydroxypropan-2-yl)-5-methylcyclohexan-1-ol). The structure of PMD is shown below. V^OH OH 15 Note that PMD may exist in a number of different stereoisomeric forms. The natural oils may be refined in order to increase the PMD content; the refined oils may be sold under a variety of trade names, including Citridiol (Registered Trademark, RTM). It is believed that the natural oils may contain a mixture of different stereoisomers 20 in varying ratios, depending on the source of the oil. It is also possible to use synthetic PMD; for example, synthetic PMD may be obtained as described by Zimmerman and English in J. A. C. S. 75 (1953) pp 2367-2370. PMD is also a precursor obtained during the synthesis of menthol. The precursor is usually in 25 the form of a specific isomer of PMD. As well as having insect-repellent properties, PMD is also useful as an antiviral or viricidal agent. This is described, for example, in US patent 7,872,051, which publication indicates that compositions comprising PMD are effective against influenza, Urbani 23 04 25 Severe Acute Respiratory Syndrome (Urbani SARS) and HSV-1. The suggestion is also made that, since all these viruses have a lipid envelope, the compositions may also be effective against other viruses having a lipid envelope, including coronaviruses. 5 This suggestion is also supported by recent work by the UK’s Defence Science and Technology Laboratory (Dstl), in which the effectiveness of an off-the-shelf insect repellent formulation containing PMD (Mosi-Guard (RTM) Natural spray) or Citriodiol (RTM)against the SARS-Cov2 virus - responsible for the COVID-19 pandemic - was assessed. The study reported that one minute liquid suspension tests indicated that 10 Citriodiol (RTM), ethanol, isopropanol and Mosi-guard (RTM) Natural have anti-viral activity against SARS-CoV-2 England-2 isolate if mixed with the virus in the liquid phase; and that SARS-CoV-2 England 2 isolate survival studies on latex as a ‘synthetic skin’ (which was pre-treated with Mosi-guard (RTM) Natural approximately 1 hour before testing) provided evidence of anti-viral properties against SARS-CoV-2 England-2 15 isolate. The work is reported at https: / / www.Qov.uk / qovernmenVpublications / experimental-survival-of-sars-cov-2-on-an-insect-repellent-treated-surface-3 (accessed 2 December 2020). It would be useful to provide formulations comprising PMD suitable for use as antiviral 20 agents. However, off-the-shelf products intended for use as insect repellents, or other Citriodiol (RTM)-containing products such as sunscreens, are generally inappropriate for repurposing as antiviral agents, for reasons including mode of application, consistency, stability, and so on. Furthermore, insect repellent formulations typically have relatively high levels of Citriodiol (RTM) - up to 30% - and may contain additional components. 25 It is therefore an object of the present invention to provide PMD formulations for use as antiviral agents. Particularly preferred formulations are stable and sprayable, to enable easy transport, storage, and application over a wide area. In other embodiments, a stable formulation as described herein may be incorporated into a non-sprayable preparation 30 such as a cream, gel, or lotion, for topical application to the skin. SUMMARY OF THE INVENTION The present invention provides a number of embodiments of formulations comprising PMD which are believed to be suitable for use as antiviral agents. While preferred 35 embodiments should be stable and sprayable (for example, as a mist or a fog) to allow 23 04 25 wide coverage, in other embodiments the formulation may be incorporated into a non-sprayable preparation, for example for topical application to the skin. It was found when researching possible formulations that PMD showed a tendency to crystallise, in particular when used at concentrations lower than those which may be found in 5 conventional insect repellents, such that potential formulations required to be modified in order to reduce crystallisation. The skilled person will appreciate that crystallised PMD may interfere with spray delivery mechanisms, so this may be a significant obstacle to practical widespread use as an antiviral; or of course may reduce the effectiveness of a preparation as an antiviral. 10 Certain antiviral compositions of the invention are intended to be sprayable. Thus, the compositions can be delivered from non-aerosol mechanical pump spray devices or from pressurized aerosol canisters using a propellant or from any other mechanism or method of dispersing compositions. The compositions may be intended for topical application to 15 the skin, and / or for application to surfaces, and / or for misting to fill a volume. A wide range of mechanical pump spray devices and aerosol canister systems are well known to those of ordinary skill in the art. Similarly, a wide range of propellant materials are well known to those skilled in the art. Nonlimiting examples include lower molecular weight hydrocarbons such as propane n-butane and isobutane, nitrogen, carbon dioxide, nitrous 20 oxide, and so forth, as well as compressed or pressurised air. Mixtures of such propellants can also be used. Unless otherwise indicated, the concentrations of ingredients specified below are given in terms of the weight of the ingredient based on the weight of the sprayable antiviral 25 composition as a whole but excluding any propellant that might be present. According to a first aspect of the present invention, there is provided an antiviral composition, the composition comprising: a) from 0.5% to 10% by weight of the total composition of p-Menthane-3,8-dio5 (PMD); 30 b) one or more solvents selected from propan-2-ol and propane-1,2-diol, and combinations thereof, wherein the amount of solvent is from 10-20% by weight of the total weight of the composition when a single solvent is present and wherein the amount of solvent is from 20-40% by weight of the total weight of the composition when a combination of solvents are present; c) either i) from 0.5% to 10% by weight of the total composition of a glyceride-based emulsifier; or ii) from 10% to 30% by weight of the total composition of a non-ionic ethoxylated sorbitan ester surfactant. It is to be understood that the term "antiviral", as used herein, means "having the capacity to inhibit or stop the growth and reproduction of viruses", or "having the capacity to destroy or inactivate viruses". 23 04 25 10 The composition may further optionally comprise: d) from 2% to 10% by weight of a polar ester selected from C12-15 alkyl benzoate, Butyl Stearate, Butyloctyl Salicylate, C12-13 Alkyl Lactate, Cetearyl Ethylhexanoate, Cetearyl Isononanoate, Cetearyl Nonanoate, Cetyl Dimethyloctanoate, Cetyl Ethyl hexanoate, Cetyl Isononanoate, Cetyl Palmitate, Decyl Isostearate, Decyl 15 Oleate, Diethyl hexyl Adipate, Diethyl hexyl Carbonate, Diisopropyl Adipate, Diisostearyl Malate, Ethyl Oleate, Ethylhexyl Palmitate, Isocetyl Ethylhexanoate, Isocetyl Isodecanoate, Isocetyl Stearoyl Stearate, Isodecyl Ethylhexanoate, Isodecyl Isononanoate, Isodecyl Neopentanoate, Isononyl Isononanoate, Isopropyl Acetate, Isopropyl Arachidate, Isopropyl Behenate, Isopropyl Benzoate, Isopropyl Citrate, 20 Isopropyl Cyanoacrylate, Isopropyl Cyclohexylpropionate, Isopropyl Hydroxystearate, Isopropyl Isostearate, Isopropyl Laurate, Isopropyl Linoleate, Isopropyl Maleate, Isopropyl Myristate, Isopropyl Nicotinate, Isopropyl Oleate, Isopropyl Palmitate, Isopropyl Pelargonate, Isopropyl Ricinoleate, Isopropyl Sorbate, Isopropyl Stearate, Isopropylacrylamide, Isopropylbenzyl Salicylate, lsosteareth-3 Ethylhexanoate, 25 Isostearyl Ethylhexanoate, Isostearyl Isononanoate, Isostearyl Isostearate, Isostearyl Neopentanoate, Isotridecyl Isononanoate, Myristyl Lactate, Myristyl Myristate, Octyldodecyl Lactate, Octyldodecyl Stearate, Phenethyl Benzoate, PPG 3 Benzyl Ether Myristate, Propylene Glycol Dibenzoate, Stearyl Caprylate, Stearyl Heptanoate, Triethylhexanoin, Triisononanoin, Triisopropyl Citrate, and Triisopropyl Trilinoleate; 30 and / or e) from 0.1% to 3% of an emulsion stabiliser (non-limiting examples include carbomers, cellulose gun, xanthan gum and microcrystalline cellulose). 23 04 25 In preferred embodiments, the composition consists essentially of components a) to c), and optionally d) and / or e), and water. That is, no additional components are present. In particular, though not encompassed by the wording of the claims, this means the composition can be provided as an oil-free, and (in some embodiments) ethanol-free 5 composition. In other embodiments, though not encompassed by the wording of the claims, the composition may consist essentially of components a) to c), and optionally d) and / or e), and water, and further optional ingredients to improve shelf life and aesthetic properties. 10 The composition may be in the form of an emulsion, when an emulsifier is used, or in the form of a solution, where no emulsifier is used. Preferred embodiments provide the composition as a solution, since this is easier to handle and manipulate, but there may be some circumstances when an emulsion is preferred. In particular, an emulsion may be preferable when the composition is to be formulated on site (for example, to be 15 prepared by the end user or an intermediary), rather than being centrally manufactured and distributed. The PMD present in the composition may be any single isomer or any combination of one or more isomers. In preferred embodiments, the PMD is at least 90%, 92%, 93%, 20 94%, 95%, or more of a pure single isomer. However, we believe that the relevant antiviral properties are not dependent on a particular isomer, such that other degrees of purity or mixtures of isomers may be used. The amount of PMD present in the composition may be from 0.5%-10%, alternatively 25 1%-9%, preferably 2%-8%, or 3%-7%, or 4%-6%. In preferred embodiments, the composition comprises 5% by weight of PMD. The solvent may be selected from propan-2-ol and propane-1,2-diol, and combinations thereof. 30 The solvent may be present from 10-20% by weight of the total weight of the composition when a single solvent is present and from 20-40% by weight of the total weight of the composition when a combination of solvents are present. In one embodiment, wherein the one or more solvents is a combination of propan-2-ol and propane-1,2-diol, and the 35 combination comprises 25-35% by weight of the total weight of the composition. 23 04 25 One example of a preferred composition includes 25% propan-2-ol and 5% propane-1,2-diol; this is more preferred where the composition is not an emulsion. Hence in a further 5 embodiment, when the solvent is or includes propane-1,2-diol, component c) is not an emulsifier. We have found that propan-2-ol alone is an efficient solvent, but that addition of propane-1,2-diol can help to reduce loss by evaporation and the propensity for the PMD to crystallise and potentially block dispensing of the composition. 10 The glyceride-based emulsifier, when present, may be present at 0.5-10% by weight of the total composition. In one embodiment, the glyceride-based emulsifier is present at 1.5-3.5% by weight of the total composition. Preferred emulsifiers include polyglycerylester emulsifiers or glyceryl esters of fatty acids; one particularly preferred emulsifier is glyceryl oleate citrate, with alternatives being glyceryl stearate citrate or glyceryl cocoate 15 citrate. Commercially-available emulsifiers may be used; for example, that available under the brand “dermofeel (RTM) easymuls plus” from Evonik (which contains glyceryl oleate citrate). Other emulsifiers which may be suitable include: the “Sucrabase” range produced by Alfa Chemicals (comprising caprylic / capric triglycerides, glycerine, sucrose laurate, sucrose stearate); DUB Base Expert+ from Stearinerie Dubois (containing 20 glyceryl stearate citrate, sucrose stearate, polyglyceryl-4 cocoate, cetyl alcohol, sodium ricinoleate). Where commercial formulations of emulsifiers are used, it is preferred that these are PEG free. The non-ionic ethoxylated sorbitan ester surfactant, when present, may be present at 25 10-30% by weight of the total composition. In one embodiment, the non-ionic ethoxylated sorbitan ester surfactant is present at 10-20% by weight of the total composition. Preferred surfactants are polysorbates, in particular polysorbate 80, but in certain embodiments other polysorbates may be used such as polysorbate 20, polysorbate 40, polysorbate 60. Polysorbates are a class of surfactant comprising ethoxylated esters. 30 Polysorbate 80 is a mixture of oleate esters of sorbitol and sorbitol anhydrides, consisting predominantly of the monoester, condensed with approximately 20 moles of ethylene oxide. It is also known as Polyoxyethylene (20) Sorbitan Monooleate. The higher the degree of ethoxylation the more likely it will be a good solubiliser. 23 04 25 In certain embodiments, a polar ester may be present, from 2% to 10% by weight; preferably from 3-9%, from 4-8%, or most preferably 5%. We have found that addition of such an ester may help reduce crystallisation of the PMD. The polar ester is selected from Butyl Stearate, Butyloctyl Salicylate, C12-13 Alkyl Lactate, Cetearyl Ethylhexanoate, Cetearyl Isononanoate, Cetearyl Nonanoate, Cetyl Dimethyloctanoate, Cetyl Ethylhexanoate, Cetyl Isononanoate, Cetyl Palmitate, Decyl Isostearate, Decyl Oleate, Diethyl hexyl Adipate, Diethyl hexyl Carbonate, Diisopropyl Adipate, Diisostearyl Malate, Ethyl Oleate, Ethylhexyl Palmitate, Isocetyl Ethylhexanoate, Isocetyl Isodecanoate, Isocetyl Stearoyl Stearate, Isodecyl Ethylhexanoate, Isodecyl Isononanoate, Isodecyl Neopentanoate, Isononyl Isononanoate, Isopropyl Acetate, Isopropyl Arachidate, Isopropyl Behenate, Isopropyl Benzoate, Isopropyl Citrate, Isopropyl Cyanoacrylate, Isopropyl Cyclohexylpropionate, Isopropyl Hydroxystearate, Isopropyl Isostearate, Isopropyl Laurate, Isopropyl Linoleate, Isopropyl Maleate, Isopropyl Myristate, Isopropyl Nicotinate, Isopropyl Oleate, Isopropyl Palmitate, Isopropyl Pelargonate, Isopropyl Ricinoleate, Isopropyl Sorbate, Isopropyl Stearate, Isopropylacrylamide, Isopropylbenzyl Salicylate, lsosteareth-3 Ethylhexanoate, Isostearyl Ethylhexanoate, Isostearyl Isononanoate, Isostearyl Isostearate, Isostearyl Neopentanoate, Isotridecyl Isononanoate, Myristyl Lactate, Myristyl Myristate, Octyldodecyl Lactate, Octyldodecyl Stearate, Phenethyl Benzoate, PPG 3 Benzyl Ether Myristate, Propylene Glycol Dibenzoate, Stearyl Caprylate, Stearyl Heptanoate, Triethylhexanoin, Triisononanoin, Triisopropyl Citrate, and Triisopropyl Trilinoleate. Particularly preferred examples may include Decyl Oleate, Diethyl hexyl Carbonate, Isopropyl Benzoate, Isopropyl Citrate, Isopropyl Myristate, and Isopropyl Palmitate. Particularly preferred embodiments of the invention are, first, an antiviral composition comprising: a) from 3-7% by weight of the total composition of p-Menthane-3,8-diol (PMD); b) 15-20% by weight of the total composition of propan-2-ol; c) 10% by weight of the total composition of polysorbate 80, and, optionally d) 10% by weight of the total composition of propane-1,2-diol, when component b) is present at 20% by weight of the total composition. 23 04 25 A second particularly preferred embodiment is an antiviral composition comprising: a) 5% by weight of the total composition of p-Menthane-3,8-diol (PMD); b) 15-30% by weight of the total composition of propan-2-ol; 5 c) from 10% to 20% by weight of the total composition of polysorbate 80; and d) 0-10% by weight of the total composition of propane-1,2-diol; wherein, when propane-1,2-diol is present, the total combined amount of propane-1,2-diol and propan-2-ol is 30% by weight of the total composition 10 A third particularly preferred embodiment is an antiviral composition comprising: a) 5% by weight of the total composition of p-Menthane-3,8-diol (PMD); b) 10-15% by weight of the total composition of propane-1,2-diol; c) 0-5% by weight of the total composition of a polar ester; d) 1-5% by weight of the total composition of an emulsifier; and 15 e) 0.1% to 3% by weight of the total composition of an emulsion stabiliser. A further aspect of the invention not encompassed by the wording of the claims provides a concentrate which, when diluted with water, yields a sprayable antiviral composition as defined herein. The concentrate cannot be water-free but will preferably contain a 20 minimum amount of water required to provide a stable solution or paste. This can then be diluted as required to yield the composition. In certain embodiments, we believe that a maximum of 25% by weight of water in the concentrate is preferred. A still further aspect of the invention not encompassed by the wording of the claims 25 provides a spray bottle containing a composition as defined herein. Further aspects of the invention relate to the incorporation of compositions as described into a (preferably non-sprayable) formulation for topical application to the skin; for example, a gel, cream, or lotion. Incorporation of the composition into a gel, cream, or 30 lotion for topical application to the skin allows for a longer-term barrier preparation to be used, which we believe in turn will permit longer lasting antiviral effects. The stable antiviral compositions as described may be added to a suitable base for a gel, cream, or lotion; such bases will be known to those of skill in the art. For example, a simple face cream base may include water, emulsifying wax, and oil, in appropriate proportions to 35 achieve a desired thickness of the cream. Examples of emulsifying waxes may include 23 04 25 Emulsimulse (Glyceryl Stearate, Cetearyl Alcohol, and Sodium Stearoyl Lactylate); Emulsifying Wax NF (Cetostearyl Alcohol and Polysorbate 60) ;Polawax (Cetearyl Alcohol, PEG-150 Stearate, Polysorbate 60, and Steareth-20). A suitable proportion may be 75% water, 10% emulsifying wax, 5% other oil, and 10% sprayable antiviral 5 composition as defined herein. Lotions and creams are typically oil or wax based, with the difference being that creams may be “heavier”; while gels are typically water based with a gelling agent (eg, xanthan gum, SDS, carrageenan, and so on). The exact composition of the base is not believed to be critical to the current invention, and the skilled person will be aware of suitable ingredients for cosmetic preparations for creams, 10 lotions, or gels for topical application to the skin. Any dermatologically-acceptable carrier or base preparation may be used. Further, “neutral” cosmetic bases can be purchased ready-made from various suppliers. In preferred embodiments, not encompassed by the wording of the claims, the antiviral 15 composition includes a relatively high level of PMD (for example15%, 20%, 25%), to account for the dilution resulting from incorporation into a gel, cream, or lotion. Thus, in another aspect of the invention, there is a gel, cream, or lotion composition for topical application to the skin, the composition comprising an antiviral composition as 20 described herein. In a final aspect of the invention, there is a method of making a gel, cream or lotion composition for topical application to the skin, the method comprising providing a cosmetic gel, cream, or lotion base preparation, and combining the base preparation with 25 an antiviral composition as described herein. EXAMPLES The following examples are intended to illustrate aspects of the invention, and to describe how it may be practiced. They are not intended to limit the scope of the 30 invention. We aimed to identify ways to solubilise or emulsify PMD into a water-thin solution or emulsion that can be sprayed in a fog. Ideally the ingredients were to be readily available and the formula be suitable for cold-processing, thereby allowing production in many 23 04 25 different environments and circumstances (for example, in temporary hospitals, or in remote or underserved areas of the world). Our research made use of a commercially available PMD solution, from Chemical 5 Process Laboratories, Silverton, South Africa which was specified as being 70-75% active by weight. On analysis, the test sample as received was 71% active. Our objective was to provide an emulsion / solution with 5% active content; hence the following examples indicate use of 7.15% PMD solution to give a final 5% active content. Alternative sources of PMD may of course be used, and in particular when scaling up for 10 larger production runs it is possible to commercially obtain PMD Solution with a range of 55% to 75% and up to 95-97% pure PMD in solid form. The reason for selecting 5% active is to ensure sufficient PMD is present in the applied final product, assuming some inevitable variation in surface skin moisture, inconsistency 15 of application, and so on. However, PMD is believed to provide antiviral effects across a range of concentrations. The insect repellent effect is only seen at much higher concentrations, and hence most existing PMD-containing formulations are geared towards stability at these higher (up to 30%) concentrations. 20 Formula Development Previous experience with Citriodiol (RTM) in formulations for insect repellents was expected to be relevant in reaching the goal. However, the formulation process proved to be unexpectedly complex. One particular issue was that a blend of solubilisers that worked when added with Citriodiol (RTM) at 30% did not work when in the same 25 proportion with PMD Solution at 7.15%. After further consideration of potential formulations, some were prepared but overnight storage at 5C showed crystals developing in most of them; hence these were considered unsuitable. After further development, four possible solutions were obtained, and were tested at 5C, 30 ambient and 40C. After 5 days all were clear at ambient and 40C but three showed different levels of crystal development at 5C. Concurrent with trying to find clear solutions we also looked at various emulsifier possibilities and two were identified that appeared promising. These were also tested for 5 days at the 3 conditions. One emulsion showed signs of instability but the other one remained stable for the full 10 days test period. Table 1 below shows the components of two test emulsions, and four test solutions, and the results after 10 days storage at the three temperature conditions. One emulsion (F1 / 7229B) appeared stable after 10 days at 40C and one solution (F1 / 7743C) showed 5 no sign of crystals after 10 days at 5C. We determined that both propylene glycol (PG) and isopropanol (I PA) show solvent properties for PMD Solution. 23 04 25 Table 1: Tested Samples Emulsions Solutions Ingredients F1 / 7229 B F1 / 7229 C F1 / 7729 A F1 / 7743 B F1 / 7743 C F1 / 7743 D PMD Solution 7.15 7.15 7.15 7.15 7.15 7.15 Propylene Glycol 15.00 10.00 10.00 0 0 20.00 Easymuls Plus* 2.50 0 0 0 0 0 Water 75.35 80.35 42.85 47.85 61.35 56.55 Lysofix Liquid 0 2.5 0 0 0 0 Isopropanol 0 0 30.00 0 15.00 0 Polysorbate -60** 0 0 10.00 0 0 0 Polysorbate -80*** 0 0 0 0 16.50 16.30 Butylene Glycol 0 0 0 30.00 0 0 Crodasol WS 0 0 0 15.00 0 0 100% 100% 100% 100% 100% 100% 10-day Storage 5C crystals? Clear Crystals visible V. slight crystals Cloudy Clear Slight crystals Ambient Stable Stable Clear Clear Clear Clear 40C Stable Unstable Clear Clear Clear Clear Following this investigation and previous screening processes Easymuls plus is the emulsifier of choice. It is Glyceryl Oleate Citrate from Evonik, described as a natural, anionic PEG-free O / W emulsifier for low-viscous products. It shows excellent cold 5 emulsifying capacities and can stabilise oil contents from 5 % to 30 % without significantly increasing the emulsion viscosity, making it very suitable for a spray application. Of the many solubilisers tried Polysorbate-80 was the most effective but it was present 10 at quite a high level. We next looked at reducing its level to 10% and adjusting levels of propylene glycol and isopropanol to find the optimum blend when used at 30% in a formulation - see Table 2. Table 2: To find Optimum Blend of IPA / PG. 23 04 25 Ingredients Blend 1 Blend 2 Blend 3 Blend 4 PMD Solution 7.00 7.00 7.00 7.00 Polysorbate-80 10.00 10.00 10.00 10.00 I PA 30.00 20.00 10.00 0.00 PG 0 10.00 20.00 30.00 Water, deionised 53.00 53.00 53.00 53.00 Storage Results Cloudy when mixed Cloudy when mixed 5C Clear Clear Ambient Clear Clear 40C Clear Clear We were left with one emulsion and three solutions that appeared to fulfil our requirements, they remained stable for a minimum of 10 days and were each sprayed through perfume atomisers without a problem. 20 We only had one emulsion under test and previous work showed the advantage of using a polar ester to improve stability and inhibit crystal formation. Further samples were prepared using three different esters; C12-15 Alkyl Benzoate, Decyl Oleate and Ethylhexyl Carbonate and these were put under test as before. There are three solutions; the preference is for F1-7744 B using both PG and I PA. PG 5 will slow evaporation rate and inhibit crystals forming in the spray nozzle after use. 23 04 25 Table 3 Emulsions Solutions Ingredients F1 / 722 9B F1 / 776 4A F1 / 776 4B F1 / 776 4C F1 / 774 3C F1 / 774 4 A F1 / 774 4 B PMD Solution 7.15 7.15 7.15 7.15 7.15 7.15 7.15 Propylene Glycol 15.00 10.00 10.00 10.00 0 0 10.00 Easymuls Plus* 2.50 3.00 3.00 3.00 0 0 0 C12-15 Alkyl benzoate 0 5.00 0 0 0 0 0 Decyl Oleate 0 0 5.00 0 0 0 0 Diethyl Hexyl Carbonate 0 0 0 5.00 0 0 0 Water 75.35 74.85 74.85 74.85 61.35 52.85 52.85 Isopropanol 0 0 0 0 15.00 30.00 20.00 Polysorbate- 80 0 0 0 0 16.50 10.00 10.00 100% 100% 100% 100% 100% 100% 100% Experiments have also been carried out on preparing concentrates for emulsions. 10 Examples of concentrates are shown in Table 4 below. Table 4: Concentrates - to be diluted 40% concentrate / 60% water. Ingredients F1 / 7764A F1 / 7764B PMD Solution 17.875 17.875 Propylene Glycol 37.5 37.5 Easymuls Plus* 7.125 7.125 C12-15 Alkyl benzoate 12.50 0 Decyl Oleate 0 12.50 Water 25.00 25.00 100% 100% 23 04 25 5 Barrier preparations Having prepared various stable formulations comprising PMD, primarily with the aim of making a sprayable antiviral composition, we realised that the stable formulation could additionally be used as a base ingredient in potentially longer-lasting barrier preparations (for example, skin creams, lotions, or gels). These have the advantage of possibly 10 improved compliance (as they can be directly applied to the skin rather than sprayed in a general environmental misting), longer lasting effects (given that the barrier preparation will remain on the skin rather than evaporating), and a wider range of applications. Further, this retains the advantages of the stable preparation, since this may be prepared at one location, and combined with a cream, lotion, or gel base preparation at another, 15 to allow for suitable distribution networks. Accordingly, we will test the emulsions, solutions, and concentrates described herein in combination with cosmetic bases for creams, lotions, and gels. Even where the initial stable preparation contains 5% PMD, this is believed to still be capable of providing 20 antiviral effects even when diluted ten- or twenty-fold in a cream, gel, or lotion base. One example cream formulation for topical application comprises ingredient % weight Xanthan gum 0.3 PMD 100% active 5 C12-15 Alkyl Benzoate 5 Propylene Glycol 10 Capric / Caprylic Triglyceride 5 Diisopropyl Adipate 10 OLIVEM 1000 ( Cetearyl Olivate + Sorbitan Olivate) 4.5 OLI WAX LC (Cetyl Palmitate, Sorbitan Palmitate, Sorbitan Olivate) 4.5 Water To 100% 23 04 25 23 04 25

Claims

1. An antiviral composition, the composition comprising:a) from 0.5% to 10% by weight of the total composition of p-Menthane-3,8-diol 5 (PMD);b) one or more solvents selected from propan-2-ol and propane-1,2-diol, and combinations thereof, wherein the amount of solvent is from 10-20% by weight of the total weight of the composition when a single solvent is present and wherein the amount of solvent is from 20-40% by weight of the total weight of the composition when a 10 combination of solvents are present;c) either i) from 0.5% to 10% by weight of the total composition of a glyceride-based emulsifier; orii) from 10% to 30% by weight of the total composition of a nonionic ethoxylated sorbitan ester surfactant.

152. The composition of claim 1, further comprising:d) from 2% to 10% by weight of a polar ester, selected from C12-15 alkyl benzoate, Butyl Stearate, Butyloctyl Salicylate, C12-13 Alkyl Lactate, Cetearyl Ethylhexanoate, Cetearyl Isononanoate, Cetearyl Nonanoate, Cetyl Dimethyloctanoate, 20 Cetyl Ethylhexanoate, Cetyl Isononanoate, Cetyl Palmitate, Decyl Isostearate, Decyl Oleate, Diethyl hexyl Adipate, Diethyl hexyl Carbonate, Diisopropyl Adipate, Diisostearyl Malate, Ethyl Oleate, Ethylhexyl Palmitate, Isocetyl Ethylhexanoate, Isocetyl Isodecanoate, Isocetyl Stearoyl Stearate, Isodecyl Ethylhexanoate, Isodecyl Isononanoate, Isodecyl Neopentanoate, Isononyl Isononanoate, Isopropyl Acetate, 25 Isopropyl Arachidate, Isopropyl Behenate, Isopropyl Benzoate, Isopropyl Citrate, Isopropyl Cyanoacrylate, Isopropyl Cyclohexylpropionate, Isopropyl Hydroxystearate, Isopropyl Isostearate, Isopropyl Laurate, Isopropyl Linoleate, Isopropyl Maleate, Isopropyl Myristate, Isopropyl Nicotinate, Isopropyl Oleate, Isopropyl Palmitate, Isopropyl Pelargonate, Isopropyl Ricinoleate, Isopropyl Sorbate, Isopropyl Stearate, 30 Isopropylacrylamide, Isopropylbenzyl Salicylate, lsosteareth-3 Ethylhexanoate, Isostearyl Ethylhexanoate, Isostearyl Isononanoate, Isostearyl Isostearate, Isostearyl Neopentanoate, Isotridecyl Isononanoate, Myristyl Lactate, Myristyl Myristate, Octyldodecyl Lactate, Octyldodecyl Stearate, Phenethyl Benzoate, PPG 3 Benzyl Ether Myristate, Propylene Glycol Dibenzoate, Stearyl Caprylate, Stearyl Heptanoate,23 04 25Triethylhexanoin, Triisononanoin, Triisopropyl Citrate, and Triisopropyl Trilinoleate and / or 0.1% to 3% of an emulsion stabiliser.

3. The composition of any preceding claim, consisting essentially of components a) 5 to c) and water, and optionally components d) and / or e).

4. The composition of any preceding claim comprising 5% by weight of PMD.

5. The composition of any preceding claim wherein the one or more solvents is a10 combination of propan-2-ol and propane-1,2-diol, and the combination comprises 25-35% by weight of the total weight of the composition.

6. The composition of claim 5 wherein the composition comprises 25% propan-2-ol and 5% propane-1,2-diol.

157. The composition of any preceding claim wherein the solvent is or includes propane-1,2-diol, and component c) is a non-ionic ethoxylated sorbitan ester surfactant.

8. The composition of any of claims 1-6 wherein the glyceride-based emulsifier is 20 present at 1.5-3.5% by weight.

9. The composition of any preceding claim wherein the non-ionic ethoxylated sorbitan ester surfactant is present at 10-20% by weight.25 10. The composition of any preceding claim wherein the non-ionic ethoxylatedsorbitan ester surfactant comprises polysorbate 80.

11. An antiviral composition according to claim 1, the composition comprising:a) from 3-7% by weight of the total composition of p-Menthane-3,8-diol (PMD);30 b) 15-20% by weight of the total composition of propan-2-ol;c) 10% by weight of the total composition of polysorbate 80, and, optionallyd) 10% by weight of the total composition of propane-1,2-diol, when component b) is present at 20% by weight of the total composition.3523 04 2512. An antiviral composition according to claim 1, the composition comprising:a) 5% by weight of the total composition of p-Menthane-3,8-diol (PMD);b) 15-30% by weight of the total composition of propan-2-ol;c) from 10% to 20% by weight of the total composition of polysorbate 80; and5 d) 0-10% by weight of the total composition of propane-1,2-diol; wherein, whenpropane-1,2-diol is present, the total combined amount of propane-1,2-diol and propan-2-ol is 30% by weight of the total composition.

13. An antiviral composition according to claim 2, the composition comprising:10 a) 5% by weight of the total composition of p-Menthane-3,8-diol (PMD);b) 10-15% by weight of the total composition of propane-1,2-diol;c) 0-5% by weight of the total composition of a polar ester;d) 1-5% by weight of the total composition of an emulsifier; ande) 0.1% to 3% by weight of the total composition of an emulsion stabiliser.1514. A gel, cream, or lotion composition for topical application to the skin, the composition comprising an antiviral composition as defined in any of claims 1-13.

15. A method of making a gel, cream or lotion composition for topical application to20 the skin, the method comprising providing a cosmetic gel, cream, or lotion base preparation, and combining the base preparation with an antiviral composition as defined in any of claims 1-13.25