A sprayable formulation for use in the prevention of viral infections and / or allergic reactions

Abstract

A sprayable formulation (2) for use in reducing or preventing viral infections and / or allergic reactions is disclosed, wherein the formulation comprises a barrier-forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material comprises a naturally non-sulphated polysaccharide or derivative thereof, and the formulation does not comprise any additional materials which exhibit antiviral or antiallergy activity. Also disclosed is a formulation which does not comprise carrageenan, and a formulation wherein the barrier-forming material substantially consists of a naturally non-sulphated polysaccharide or derivative thereof. A spray device comprising the formulation is also disclosed.

Description

A SPRAYABLE FORMULATION FOR USE IN THE PREVENTION OF VIRAL INFECTIONS AND / OR ALLERGIC REACTIONS

[0001] The present invention relates to a sprayable formulation for use in the prevention of viral infections and / or allergic reactions.

[0002] The COVID-19 pandemic was a generational challenge to worldwide health systems. In response, there has been an acceleration in the rate of innovation, including targeted therapeutic and vaccine development. There remains, however, latency between viral infection / spread throughout human populations, and the development of such targeted interventions. As such, the potential for novel viruses to cause widespread mortality prior to the development of therapeutics is still significant. Moreover, once a virus becomes endemic, there is the risk of rapid mutation leading to the production of ever-more infectious strains that continue to have a significant effect on public health.

[0003] Non-specific prophylactic measures to prevent widespread infection have included an increased awareness of hygiene practices (such as correct handwashing procedures), the adoption of and innovation in face masks, and recent developments in nasal spray technologies to reduce the likelihood and / or severity of infection. Regarding the latter, a range of nasal spray formulations were developed during the COVID-19 pandemic focused on reducing viral transmission, resulting in an increase in the diversity of nasal applicants, including anti-viral mechanisms by the generation of free radicals, acidification of the nasal mucosa, and barrier functions that target physical interference between viral binding and surface receptorswhich mediate uptake across the mucosa.

[0004] To this end, a range of carrageenan-based products have been reported, carrageenan being a molecule which is known to inhibit viral infection. For example, WO 2022 / 084533 discloses a sprayable antiviral formulation comprising carrageenan in a carrier polymer demonstrating large spray coverage, viscosity and intrinsic anti-viral activity. However, more recently the SARS-CoV-2 – a positive strand RNA virus – has undergone significant mutation, with numerous single-point mutations throughout the viral genome. It is the mutations in the viral surface glycoprotein, namely spike (S), that are most important to the enhanced infectivity of the virus. The S protein plays a significant role in the viral entry to the host cells, and is divided into two main parts: S1, containing the receptor binding domain (RBD), and S2 which mediates the viral fusion with the host cell membrane. Each viral strain subsequent to the ancestral, for example Alpha, Beta, Gamma, etc. arose following different, although overlapping, mutations in the aforementioned protein, driving substantial waves of infection throughout the population. Indeed, a particular rise in infectivity was seen following a mutation that favoured the entry of the virus via the endocytic pathway, rather than the cellular protease (TMPRSS2). These rapid mutations highlight the challenges to targeted interventions, resulting in significant reductions in the efficacy of their treatments, and the need for multiple approaches which are not dependent on specific chemistries / biochemistries.

[0005] According to the present invention in a first aspect there is provided a sprayable formulation for use in reducing or preventing viral infections and / or allergicreactions, wherein the formulation comprises a barrier- forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material comprises a naturally non-sulphated polysaccharide or derivative thereof, and the formulation does not comprise any additional materials which exhibit antiviral or antiallergy activity.

[0006] According to the present invention in a second aspect there is provided a sprayable formulation for use in reducing or preventing viral infections and / or allergic reactions, wherein the formulation comprises a barrier- forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material comprises a naturally non-sulphated polysaccharide or derivative thereof, and the formulation does not comprise carrageenan.

[0007] According to the present invention in a third aspect there is provided a sprayable formulation for use in reducing or preventing viral infections and / or allergic reactions, wherein the formulation comprises a barrier- forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material substantially consists of a naturally non-sulphated polysaccharide or derivative thereof. Herein “substantially consists of” means that the barrier-forming material does not contain a material other than a non-sulphated polysaccharide or derivative thereof which materially contributes to barrier-formation.

[0008] For the avoidance of doubt, sprayable formulations comprising combinations of the first and second, the second and third, the first and third, and the first, second and third aspects of the present invention are also within the scope of the present invention.

[0009] The term “naturally non-sulphated” as used herein means that the polysaccharide in its natural (native) state is not sulphated, and the term “derivative” means a compound which is a modified version of the naturally non-sulphated polysaccharide, for example by substitution or replacement of an atom of group of atoms of the naturally non-sulphated polysaccharide for another atom or group of atoms. Thus, by way of example, sulphated gellan (a naturally non-sulphated polysaccharide) is a gellan derivative. For the avoidance of doubt, a derivative of a naturally non-sulphated polysaccharide may be produced by reaction of the naturally non-sulphated polysaccharide with another reagent, or may be produced from other reagents not involving the naturally non- sulphated polysaccharide.

[0010] Accordingly, the present invention provides sprayable formulations which form a physical barrier when contacted with, for example, the oral or nasal mucosal membrane of a subject, or for example the tear film, cornea, conjunctiva, blood-ocular and blood-retina barriers of their eye, and thereby help prevent viral infections and / or allergic reactions, the formulations comprising a naturally non-sulphated polysaccharide or derivative thereof as a barrier-forming material.

[0011] The formulation of the first aspect of the invention does not comprise any additional materials whichexhibit antiviral or antiallergy activity, for example active agents which exhibit antiviral or antiallergy activity through molecular, chemical or biochemical interaction, whether specifically targeted or otherwise, i.e. it provides an entirely physical solution to helping to prevent viral infections and / or allergic reactions. Thus, the inventors have unexpectedly found that an antiviral and / or antiallergy barrier effect may be achieved without the need for an additional active agent, such as carrageenan. Indeed, the present inventors have shown that against more infective strains of SARS-CoV-2 (e.g. Omicron, BA.1 and BA.2 strains), carrageenan alone is increasingly less effective.

[0012] The formulations of the present invention have the advantages of high mucoadhesivity and spray coverage, no requirement for a drug molecule to be present to achieve the desired effect, and the economic advantage of cheap and readily available materials.

[0013] The formulations of the present invention are sprayable compositions, for example an oral, nasal or ocular spray. The term "sprayable" as used herein is intended to mean that the formulations produce a plume of droplets rather than a jet of fluid when sprayed from a normal spray nozzle, whereas a formulation which forms a jet when sprayed may be considered to be "jettable". A jet can be considered to be a coherent stream of fluid, whereas a plume is formed when a jet disrupts to form small, discrete droplets. The jet may disrupt to form a plume of droplets either immediately after ejection from the nozzle, or at a distance away from the nozzle.

[0014] For the purposes of the present disclosure, aformulation may be deemed to be sprayable if the jet disrupts to form a plume of droplets within 0-5cm of the nozzle when sprayed. Without wishing to be bound by theory, it is thought that a formulation which forms a plume within 0-5 cm of the nozzle when sprayed creates a sufficient distribution of droplets to coat a mucosal or ocular surface within a confined interior space, such as an oral or nasal cavity. In some embodiments, where the formulation is intended for use as an oral or nasal spray, the formulation may form a plume within 0-2.5cm of the nozzle when sprayed.

[0015] In some embodiments, "sprayability" may be assessed by measuring the percentage coverage of a set area that the formulation is sprayed onto from a set distance. For example, the percentage coverage may be determined using the following procedure:

[0016] the formulation is mixed thoroughly with black ink in a falcon tube; the cap of the falcon tube is replaced with a normal spray applicator (nozzle aperture e.g. 750 μm); the applicator is primed by depressing the manual actuator multiple (e.g. 10) times; the formulation is sprayed vertically upwards, once, onto a horizontal sheet of paper suspended e.g. 10 cm away from the spray applicator nozzle; the paper is then allowed to dry before scanning, e.g. at 600 dpi in greyscale; the image is cropped around the spray distribution, using image analysis software; and the image analysis software is used to analyse the percentage of the cropped area covered by the spray.

[0017] In some embodiments, the formulation is deemed tobe "sprayable" if the percentage coverage, as determined by the above procedure, is at least 13%. In some embodiments, the percentage coverage achieved by the formulation may be at least 13%, at least 15%, at least 20%, or at least 25%. In general, the higher percentage coverage achieved by a formulation, the more sprayable the formulation may be deemed to be.

[0018] A scale bar may be applied within the image analysis software to determine the number of pixels that corresponds to 1 cm in the cropped image, such that the percentage coverage can be converted to an area in cm2. From this, the spray distribution radius can be calculated.

[0019] Using the procedure above, a formulation may be deemed to be "sprayable" if the distribution radius is at least 1.8 cm. In some embodiments, the distribution radius achieved by the formulation may be at least 1.8 cm, at least 2.0 cm, at least 2.2 cm, or at least 2.4 cm. In general, the higher the distribution radius, the more sprayable a formulation may be deemed to be.

[0020] The distribution radius and the distance that the nozzle is held from the paper when sprayed can in turn be used to determine the spray angle, i.e. the maximum angle at which droplets in the plume deviate away from a central axis along which the formulation is sprayed, using Equation 1 (where adj is the distance that the nozzle is held from the paper when sprayed and opp is the distribution radius): xo= tan-1(opp / adj) [1]

[0021] Using the procedure above, a formulation may be deemed to be "sprayable" if the spray angle is at least 10°.In some embodiments, the spray angle achieved by the formulation may be at least 10°, at least 11°, at least 12°, at least 13°, or at least 14°. In general, the higher the spray angle, the more sprayable a formulation may be deemed to be. It will be understood that, in embodiments where the jet disrupts into a plume of droplets at a distance away from the nozzle rather than immediately after ejection, the actual angle formed by the plume away from the central axis of the jet may be higher than the angle calculated from the nozzle. However, for the purposes of the present disclosure, the effective spray angle is deemed to be the angle calculated from the nozzle to the surface that the formulation is sprayed on, as if the jet had disrupted into a plume of droplets immediately upon ejection from the nozzle.

[0022] The sprayable formulations are for application to, and formation of a barrier on, a mucosal surface or ocular barrier. In some embodiments, the formulations are for use as an oral spray and / or a nasal spray. It will be understood that a formulation for use as an oral or nasal spray must be non-toxic and safe for use on mucosal surfaces. As such, it is preferred that the formulations are free or substantially free of oxidising agents commonly used for their antiviral properties, such as hydrogen peroxide, which may irritate the delicate mucosal membrane. After use, the spray may be removed by the body's natural mucus-clearing processes or manually by the user, e.g. washing an oral spray into the oesophagus by drinking a liquid such as water, or blowing the nose to remove a nasal spray.

[0023] The formulations of the present invention have a prophylactic effect to prevent infection and / or transmission of airborne viruses and / or allergens when sprayed onto asurface, by providing a physical barrier which traps virus particles and / or allergens and prevents them from passing through the sprayed layer. In some embodiments, the sprayable formulations are for use in the prevention of infection by and / or transmission of an airborne virus. In some embodiments, the airborne virus is selected from one or more of influenza-, rhino-, adeno-, entero-, Respiratory Syncytial Virus and coronavirus. In some embodiments, the sprayable antiviral formulations are for use in the prevention of infection and / or transmission of a coronavirus. In some embodiments, the coronavirus is SARS-CoV-2.

[0024] In some embodiments, the sprayable formulations are for use in the prevention of allergic reactions through the prevention of infection by and / or transmission of an airborne allergen. Some common sources of airborne allergens include dust mites, pollen, fungal spores and animals. The most common allergens causing rhinitis are pollen, spores and dust mites. Pets are also a major source of allergens, including the proteins present in their skin flakes, saliva, and urine. Pets may also collect outdoor allergens (such as pollen) in their fur, which might cause an allergic reaction that is not from the pet itself. Fungal spores are released by mold. Pollen is produced by plants as a part of their reproduction, and is a powder carried in the air to fertilize plants. Various kinds of insect matter can become airborne and trigger allergic reactions including saliva, dried feces, scales, and wings. Dust mites are a common source of airborne insect allergens. They are microscopic insects that thrive in humid areas such as furniture, carpets, and bedding. When these are disturbed, the mite allergens can become airborne. Industrial (or occupational) allergens can trigger allergies or occupational asthma, the most common work-related lungdisease in developed nations. Food allergies are typically triggered by eating the food, but airborne food allergens can be produced during food preparation and cooking, as well as in food processing facilities. Eggs, fish, peanuts, and shellfish are some of the foods that most commonly cause allergic reactions.

[0025] A protective spray should be retained on the mucosa in order to provide protection over a significant period of time. In this connection, it is known that low viscosity nasal sprays (ca. 40 mPa.s) exhibit complete clearance within 60 minutes and those with higher viscosities (ca.400 mPa.s) demonstrate a half-life closer to 2 hours. In contrast, the sprayable formulations of the present invention are able to maintain a stable viscosity with no significant clearance within the first 2 hours in situ, and preferably have an inherent half-life on mucosa of 3 to 5 hours, for example 4 hours. Preferably, the sprayable formulation remains detectable for up to 6 hours or longer (for example 7 or 8 hours) following initial application to mucosa. In this connection, the inventors have unexpectedly found that the spray formulations of the present invention structure on the mucosa as a result of interactions with the mucins, for example through synergistic effects arising through mucin- polysaccharide interactions resulting in a time-dependent “stiffening” of the sprayed layer. For example, it is thought that the sprayable formulations are able to penetrate the mucin layers, forming elastically dominated interactions, and create mucoadhesive bridges across the mucociliary blanket. The formation of a continuous entangled network is believed to prevent long range diffusion, immobilising the pathogen and allowing more efficient elimination. Thus, in preferred embodiments the inventors have found that gellan stiffens inthe presence of mucins via a 2-step process: initially, at a slower rate followed by a faster rate. The role of the spray microstructure, such as the degree of polymeric freedom to engage with the native mucins, facilitates interactions across the mucosa. This stiffening and enhanced retention on the mucosa also has advantages for use of the sprayable formulations of the present invention as a delivery vehicle for active agents, due to enhanced longevity in situ for delivery. The use of the sprayable formulations as a delivery vehicle for active agents is within the scope of the present invention.

[0026] The sprayable formulations comprise a naturally non-sulphated polysaccharide or derivative thereof which interacts with the mucous membrane and has good mucoadhesion. Good mucoadhesion helps to improve the longevity of the formulation on a mucosal surface, such as in an oral or nasal cavity, thereby extending the prophylactic effect against airborne viruses and allergens.

[0027] Without wishing to be bound by theory, it is thought that the mucoadhesive properties of the naturally non-sulphated polysaccharide or derivative thereof are not the only factor which may affect the longevity of the sprayed formulation on a surface. For example, it is preferable that the formulations do not simply flow off the surface under their own mass, particularly on inclined or inverted surfaces, and so the viscosity of the formulations may also have an effect on retention.

[0028] In some embodiments, the formulations have a dynamic viscosity of 0.05 to 100 Pa.s at 25 °C. It will be understood that individual components within the formulationsmight have a different inherent viscosity, but the dynamic viscosity of the formulations as a whole will be from 0.05 to 100 Pa.s, in some embodiments. Without wishing to be bound by theory, it is thought that in some embodiments the overall viscosity of the formulations may be affected by viscosity- modifying interactions between the individual components of the formulations as well as factors such as the concentration of individual components and overall dilution level. In some embodiments, the formulations have a dynamic viscosity of 0.05 to 50 Pa.s, 0.05 to 10 Pa.s, 0.1 to 10 Pa.s, 0.1 to 5 Pa.s, or 0.1 to 2 Pa.s, for example 0.2 Pa.s, at 25 °C. Dynamic viscosity figures are quoted at a shear rate of 1 / s.

[0029] The formulations of the present invention comprise a naturally non-sulphated mucoadhesive polysaccharide or derivative thereof. Non-limiting examples of non-sulphated polysaccharides suitable for use in the present invention include gellan, dextran, alginate, pectin and xanthan. In some embodiments, the non-sulphated polysaccharide comprises gellan or a derivative thereof. The inventors of the present invention have found that gellan provides particularly good sprayability and retention characteristics.

[0030] In some embodiments, the sprayable formulations comprise a diluent. The diluent may be used to dilute the formulations to a desired concentration, to achieve a desired level of viscosity, and / or to achieve a desired level of sprayability. The diluent may be any solvent suitable for medical use. In some embodiments, the diluent is a saline solution. For example, the saline solution may be a phosphate-buffered saline solution.

[0031] In some embodiments, the concentration of non-sulphated polysaccharide or derivative thereof in the formulations is from 0.1 to 2.0% w / v, from 0.1 to 1.5% w / v (e.g. from 0.25 to 1.5% w / v), from 0.1 to 1.0% w / v (e.g. from 0.25 to 1.0% w / v), or from 0.1 to 0.5% w / v (e.g. from 0.25 to 0.5% w / v), based on the total volume of the formulation. In general, a moderate to high total non-sulphated polysaccharide or derivative thereof content (e.g. greater than or equal to 0.4% w / v) may be desirable in order to provide a sufficiently thick and uniform layer when the formulation is sprayed onto a surface, although this must be balanced with other requirements such as sprayability, which may decrease with increasing non-sulphated polysaccharide or derivative thereof content.

[0032] In some embodiments, the formulations further comprise a dispersing agent. The dispersing agent may help to ensure homogeneity of the formulation. In some embodiments, the dispersing agent is one or more surfactants and / or salts. Examples of surfactants include phospholipids such as glycerophospholipids (e.g. lecithin), sorbitan esters, Tween 20-80, sucrose monostrate, sodium dodecyl sulphate, polysorbates and potassium sorbate. Examples of salts include monovalent salts such as those comprising sodium (e.g. NaCl) or potassium (e.g. KCl) and divalent salts such as those comprising calcium (e.g. CaCl2) or magnesium (e.g. MgSO4).

[0033] The formulations may include additional ingredients for imparting desirable properties. For example, the formulations may comprise xylitol, or hyaluronic acid and / or aloe vera for moisturising and soothing effects. A preferred embodiment may thus comprise or consist of gellan and xylitol, gellan and hyaluronic acid, or gellan and aloevera, or gellan and a combination of xylitol, hyaluronic acid and / or aloe vera. Fucoidan may be included for additional medicinal, therapeutic and blocking properties, for example a preferred embodiment may comprise or consist of gellan and fucoidan.

[0034] According to a fourth aspect of the invention, there is provided a spray device comprising a formulation of the first, second or third aspects, a body for containing the formulation therein, and a nozzle for spraying the formulation. In some embodiments, the spray device is a nasal spray device. In some embodiments, the spray device comprises a pump for ejecting the formulation from the device through the nozzle. Alternatively, the spray device may be configured so that the formulation is ejected through the nozzle when manual pressure is applied to the device, for example by squeezing the body. The construction of the spray device may be in accordance with any known spray device, and suitable constructions will be known to the person skilled in the art.

[0035] The formulations as described herein may find use in methods of prevention and / or treatment of airborne viruses, such as coronavirus, and in the reduction and / or prevention of allergic reactions. The formulations may also be used as delivery vehicles for active agents.

[0036] Embodiments of the present invention will now be described in detail with reference to the accompanying drawings, in which:

[0037] Figure 1 shows schematic diagrams showing a proposed mechanism of action for formulations according to the present invention in a nasal cavity;

[0038] Figure 2 is a schematic representation of a nasal spray, in use;

[0039] Figure 3 shows the results of nasal spray retention tests obtained from applying NoriziteTMnasal spray to the nasal cavity of healthy volunteers (n=5) to determine longevity on the nasal mucosa: (a) HPLC data used to quantify amounts of nasal spray present at each timepoint (plot shows spectra obtained for various controls used to deconvolute the mixture). (b) Elimination curve for the nasal spray detected in the nasal passages of volunteers over 8 hrs. Data plotted shows reduced data to account for variation between users. Data shows the detectable presence of the spray for up to 6 hrs). (c) Single frequency rheology of the individual spray components over time on mucosal analogues. The plot shows the difference in complex modulus for the materials when tested in the presence and absence of mucins. Data suggests that the non-sulphated polysaccharide (gellan) is structured by the mucosal surface as evidenced by a net increase in complex modulus, not observed for carrageenan. (d) Normalised shear stress against time at constant strain for the polymer blend prior to and following heat treatment assessing polymer motility in the spray form. (e) Time dependent shear stress (at constant strain) for different dilutions of the polymer blend suggesting polymer motility as a function of concentration.

[0040] Figure 4 shows the results of an assessment of the ability of NoriZite™ to resist influenza virus (H3N2);

[0041] Figure 5 shows the results of an assessment of the ability of gellan to resist influenza virus (H3N2);

[0042] Figures 6a and 6b show the results of an assessmentof the ability of gellan to resist Respiratory Syncytial Virus (RSV);

[0043] Figure 7a shows images of structures for different dyes used in the Examples; Figure 7b shows absorbance data collected using UV / Vis spectroscopy for permeation studies using NoriZite™; and Figure 7c shows absorbance data collected using UV / Vis spectroscopy for permeation studies using gellan;

[0044] Figure 8 shows the particle sizing data for the ink particles;

[0045] Figure 9 shows the results of particle trapping tests for NoriZite™;

[0046] Figure 10 shows the results of particle trapping tests for gellan;

[0047] Figure 11 shows a comparison of the adsorption spectra for NoriZite™ and gellan barrier materials; and

[0048] Figure 12 shows the results of a test performed to assess the ability of NoriZite™ to trap pollen.

[0049] Thus, Figures 1a-c show a proposed mechanism for how a formulation 2 according to the present invention may affect inhibition of SARS-Cov-2 in a nasal cavity. Figure 1a shows a nasal epithelium 100 coated in a layer of nasal spray formulation 2. The nasal epithelium 100 comprises ciliated cells 4, goblet cells 6, non-ciliated cells 8 and basal cells 10. Goblet cells 6 produce a mucus layer 12, which is cleared over time by ciliated cells 4 to drain into the throat in the direction of drainage D. Ciliated cells 4 and goblet cells 6 contain a high number of ACE2 receptors and thus areparticularly vulnerable to infection by SARS-Cov-2.

[0050] A formulation according to an embodiment of the present invention is sprayed into the nasal cavity, forming a formulation layer 2 which adheres to the mucus layer 12 and provides a physical barrier against the virus, trapping virus particles 14 within the formulation layer 2 and preventing them from infecting the ciliated cells 4 and goblet cells 6. The formulation layer 2 may be naturally cleared to drainage along with the mucus layer 12, or expelled by blowing the nose, safely removing the trapped virus particles 14 from the nasal cavity.

[0051] As shown in Figure 1b, the non-sulphated polysaccharide or derivative thereof 16 contained within the formulation 2 may create a steric barrier across the cell interface, thereby blocking virus particles 14 from entering the cells 4, 6. As shown in Figure 1c, the non-sulphated polysaccharide or derivative thereof 16 may also create a steric barrier around the interface of the virus particles 14, thereby preventing the virus from entering the cells 4, 6.

[0052] Figure 2 shows a schematic diagram of a nasal spray formulation being sprayed into the nasal cavity 20 of a user. In use, the nozzle 22 of the spray device is inserted into the nostril and actuated, e.g. by squeezing the body of the spray device or by operating a pump in the spray device. The formulation is ejected from the spray nozzle 22 into the nasal cavity 20 and coats the nasal epithelium 24 at the back of the nasal cavity 20.

[0053] Providing a prophylactic coating across the entirenasal epithelium poses a significant challenge, due to the difficulty of access via the nostrils, and the relatively large surface area and complex topology of the nasal epithelium (including inclined surfaces and ceilings). The formulation of the present invention has therefore been engineered to provide good sprayability and retention on inclined surfaces.

[0054] In a jettable formulation, the formulation is ejected from the nozzle 22 in a continuous stream or "jet" 26 along the central axis of the spray and thus only coats the nasal epithelium 24 in a concentrated location. In a sprayable formulation, in accordance with the present invention, the formulation forms a "plume" 28 of droplets, which spreads away from the central axis of the spray and coats a larger area of the nasal epithelium 24.

[0055] Example 1 - Nasal spray retention

[0056] To study longevity and barrier function, NoriZiteTMnasal spray was applied to the nasal passages of healthy volunteers (n=5), with swabs taken hourly over 8 hrs. The results of the tests are shown in Figure 3. NoriZiteTMnasal spray is a formulation comprising iota-carrageenan and gellan which is commercially available from Birmingham Biotech LTD, and described in WO 2022 / 084533.

[0057] Analysis of the spray was achieved using a digestion technique followed by HPLC (Figure 3a). Chromatograms showed that it was possible to differentiate between the nasal contaminants, sampling swab and nasal spray, where metabolites of the spray composite could be detected at ca. 11 mins. To remove inter-participantvariability (changes in natural mucus levels, mucosa surface area, etc.), relative changes in detected spray were determined and compared. Figure 3b shows elimination kinetics for the spray, demonstrating a sigmoidal response, as shown by the fit (R2= 0.98) with first order behaviour following the primary plateau (determined by a significant decrease in the area under the curve). Figure 3b shows that the formulation was retained on the surface of nasal mucosa for upwards of 6 hours, having a half-life (t0.5) of ca. 4 hours, reaching the lower level of quantification (LLOQ) by 8 hours.

[0058] To better understand the mechanism by which the spray was retained, the mechanical behaviour of the system was systematically explored using small deformation rheology (Figures 3c-e). To probe interactions between the various components and mucins present on the mucosa, analogues were prepared using gelatin on glass with / without mucins. Single frequency studies were used to determine changes in system structuring for both the gellan and carrageenan present in the NoriZiteTMnasal spray, with the data reported for the difference in complex modulus between the two analogues shown in Figure 3c. In the case of carrageenan (black circles), it can be seen that the evolution of the complex modulus was independent of the surface it was in contact with, i.e. the carrageenan had substantially the same complex modulus regardless of the presence of mucin. However, when gellan was in the presence of mucins (white diamonds in Figure 3c), there was a stiffening (44.6 Pa increase), which had yet to reach equilibrium by 5 mins. Analysis of the gradient highlighted a 2-step process, initially, at a much slower rate until ca. 70 s, where a much steeper gradient could be observed (as indicated by dotted lines). The role of the spray microstructure, specifically the degree of polymericfreedom to engage with the native mucins, facilitating interactions across the mucosa, was probed via stress relaxation. Again, similar trends were observed, this time for the composite in the absence of mucosal analogue (Figure 3d, open points). Here an exponential stress decay approached an inflection point at ca. 50-60 s. The application of a heat cycle to the spray, promoting helix formation and subsequent polymeric ordering, as a microstructural reference point, directly resulted in a change in stress-relaxation mechanical spectra (Figure 3d), causing a continual rise in stress until a maximum was reached (at 142 s) before returning to the applied stress. The extent of freedom within the spray was further investigated through dilution of the untreated sample, followed by re-testing under the same conditions (Figure 3e). Here relaxation curves demonstrated a clear dependency on spray fraction. Data was fitted to exponential decay curves (R2= >0.98 all systems), whereby a loss in both the magnitude of the stress applied, at 0.5% strain, and dissipation of the force could be seen for decreasing spray fractions (Table 1).

[0059] Table 1: Fitting coefficients for the decay ^್^^శ^^^function, ^^ = ^^^^ , to stress-relaxation plots displayed inFigure 3e. Fraction of Nasal a b c Spray (%) 100 0.0372 ±^^ × ^^^^ି^^ 39.20 ±^^. ^^^^^^^^ 29.25 ±^^. ^^^^^^^^90 0.0225 ±^^ × ^^^^ି^^ 43.10 ±^^. ^^^^^^^^ 27.64 ±^^. ^^^^^^^^80 0.0040 ±^^ × ^^^^ି^^ 23.52 ±^^. ^^^^^^^^ 14.29 ±^^. ^^^^^^^^70 0.0023 ±^^ × ^^^^ି^^ 28.04 ±^^. ^^^^^^^^ 17.03 ±^^. ^^^^^^^^60 0.0018 ±^^ × ^^^^ି^^ 20.06 ±^^. ^^^^^^^^ 14.61 ±^^. ^^^^^^^^50 0.0023 ±^^ × ^^^^ି^^ 10.29 ±^^. ^^^^^^^^ 11.82 ±^^. ^^^^^^^^

[0060] Materials and methods

[0061] Materials:

[0062] NoriZite™ nasal spray (Birmingham Biotech LTD, UK), Carrageenan (Sigma Life Science, UK), Gelatine (porcine, type A) (Sigma Life Science, UK), mucin (porcine stomach, type II) (Sigma Life Science, UK), PBS (Sigma Life Science, UK), heat inactivated FBS (Sigma Life Science, UK), Penicillin / streptomycin (Sigma Life Science, UK), Alcian blue (8GX) (Sigma Life Science, UK), Gellan gum (CG-LA) (CP Kelco), TrypLE Express 1x (Fisher Scientific), Type 1 water (Milli-Q, Merck Millipore).

[0063] Infection / Transmission analysis:

[0064] Vero cells were washed with PBS, dislodged with 0.25% Trypsin-EDTA (Sigma life sciences) and seeded into 96- well imaging plates (Greiner) at a density of 104cells per well in culture media (DMEM containing 10% FBS, 1% Penicillin and Streptomycin, 1% L-Glutamine and 1% non-essential amino acids). Cells were incubated for 24 hrs to allow time for adherence. Virus or cells were treated with polymeric solutions, diluted in media, 1 hr prior to infections. Cells were subsequently infected with SARS-CoV-2 virus England 2 stock 106IUml-1(kind gift from Christine Bruce, Public health England) diluted 1 / 150 in culture media. Cells were fixed in ice-cold MeOH after infection. Cells were then washed in PBS and stained with rabbit anti-SARS-CoV-2 spike protein, subunit 1 (The Native Antigen Company), followed by Alexa Fluor 555-conjugated goat anti-rabbit IgG secondary antibody (Invitrogen, Thermofisher). Cell nuclei were visualised with Hoechst 33342 (Thermofisher). Cells were washed with PBS and then imaged and analysed using a ThermoScientific CellInsight CX5 High-Content Screening (HCS) platform. Infected cells were scored by perinuclear fluorescence above a set threshold determined by positive(untreated) and negative (uninfected) controls.

[0065] Nasal Spray retention in healthy volunteers:

[0066] Healthy volunteers (n=5) were first swabbed to obtain baseline controls prior to the application of NoriZite™ nasal spray. Following this, volunteers applied two actuations of the spray to each nostril and were then instructed to sit quietly and gently breathe through their nose for 1 minute before resuming their normal daily routine. Swabs were obtained at 1 and 2 hrs, independently swabbing the left nostril and right, respectively. Subsequently, a minimum of 24 hrs was allowed for the nasal passage to regain homeostasis and the process repeated for 3 and 4 hrs. This was then repeated a third time for 6 and 8 hrs. Nasal swabs were flushed with 1 mL of HPLC grade water before discarding the cotton bud. Samples were then digested in equal amounts of HCl (2M) in an autoclave (TOMY-SX-700) for 20 min at 121°C (1bar). Once cooled, samples were neutralised with NaOH (2M) and passed through a 0.22 mm filter. Calibration standards were prepared in the same manner, using 100 mL of NoriZite™ in 900 mL of HPLC grade water. Post digestion and neutralisation, samples were serial diluted to create a 6- point calibration curve.

[0067] HPLC - analysis was conducted using a Thermo Separation SpectraSystem configured with an AS3000 auto sampler with column heater (set to 35°C), Phenomenex Kinetex 5µm EVO C18 100Å, P4000 gradient pump, SCM1000 degasser and UV6000LP photodiode array detector (265 nm). Mobile phase “A” comprised of HPLC grade water with formic acid (1% v) and “B” HPLC grade methanol. 100 µL of sample was injected into the system and analysed at a constant flow rate of 0.5 mL.min-1, using a 2:1 (A:B) ratio for 15 min. The column was then washedusing 100% HPLC grade methanol for 10 mins, before priming for a further 10 minutes.

[0068] Rheological characterisation: All rheological measurements were conducted on a rotational rheometer (Kinexus Ultra) at 25 °C.

[0069] Single frequency - data was obtained using mucosal analogues (gelatine with / without mucin) as the stationary plate coupled with a cone upper (4°, 40 mm diameter). Post- loading, the system was sheared, 10 s−1for 10 s, to ensure homogeneity followed by a single frequency oscillatory test, at 1 Hz and 0.5% strain.

[0070] Stress-Relaxation - was conducted using a parallel plate set up (50 mm, 0.5 mm gap) at 0.5% strain, over a 300s relaxation time. Thermal treatment was undertaken post- loading of the sample, by heating to 80°C and allowing to cool back to 25°C, before undertaking the test.

[0071] Statistical analysis: In all experiments data presented is an average of at least triplicates with error portrayed as the 95% confidence interval. Significance was determined by first assessing data for normality. Where normally distributed either: paired t-tests were conducted comparing the treatment group to the untreated control, or one-way ANOVA was conducted, comparing all groups with Holm- Sidak post hoc with pairwise analysis. Significance has been shown on plots using the following notation: n.s – not statistically different; * - p<0.05; ** - p<0.01; and, *** - p<0.001.

[0072] Example 2 – antiviral properties: NoriZite™

[0073] Tests were performed to assess the ability of NoriZite™ to resist influenza virus (H3N2) in a Transwell-24 well plate.

[0074] Materials • Influenza A virus H3N2 (NIDBVI00065) • MDCK cells • Culture medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA +1mM sodium pyruvate + 1x PS +10% FBS • Working medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA +1mM sodium pyruvate + 1μg / mL Trypsin +10% FBS • Anti-Influenza A virus Nucleoprotein antibody (GTX00858) • Secondary antibody Goat anti-Mouse IgG (H+L), Superclonal™ Recombinant Secondary Antibody, Alexa Fluor™ 488 (Invitrogen #A28175) • Millicell Hanging Cell Culture Insert, PET 1 μm, 24- well, (Millipore #PTRP24H48) • Test sample: NoriZite (Provided by Birmingham Biotech LTD)

[0075] Procedure 1. Seeding MDCK cells in 24 well plate (4x104cells / well), 37°C, incubate overnight. 2. Replace the cell culture medium with working medium (1 mL / well) and insert a Transwell into each well. 3. Add 150μl of spray or medium and 50μl virus at MOI=5 to each Transwell. Incubate at 35°C for 48 hours. 4. After 48hr remove Transwell and medium, then wash cell with PBS. 5. Fix cells with 4% Formaldehyde at room temperature for10min 6. Wash cells with PBS 7. Permeabilize cells with 0.1% Triton X-100 in PBS (room temperature, 10min) 8. Wash cells with PBST (0.05% Tween-20 in PBS) 9. Block cells with 3%BSA in PBST (room temperature, 1hr) 10. Wash cells with PBST 11. Incubate cells with anti-Influenza A Nucleoprotein 1:500 in 1%BSA / PBST, at 4℃, overnight. 12. Wash cells with PBST three times 13. Incubate cells with Goat anti-Mouse (Alexa FluorTM 488) 1:1000 in 1%BSA / PBST at room temperature, for 2hrs. 14. Wash cells with PBS three times 15. Counterstain cells with DAPI dye 16. Wash cells with PBS three times 17. Photographs were taken at 200X magnification using a fluorescent microscope, capturing five randomly selected fields

[0076] Results

[0077] The results of the H3N2 Transwell infection assay with NoriZiteTMare shown in Figure 4 and demonstrate that NoriZiteTMexhibits anti-influenza virus activity in MDCK cells. MDCK cells were infected with the H3N2 virus (MOI=5) in a Transwell-24 well plate for 48 hours with (n=3) or without (n=1) NoriZiteTM. The infected cells were stained with Influenza A virus nucleoprotein antibody (green), and the nuclei were stained with DAPI dye (blue). Representative images are shown at 200X magnification. In conclusion, the results show that after treatment with the NoriZiteTM, the number of influenza-infected MDCK cells was reduced, indicating that the NoriZiteTMhas the ability to inhibitinfluenza A (H3N2) viruses from passing through the Transwell to infect MDCK cells.

[0078] Example 3 – antiviral properties: gellan

[0079] Tests were performed to assess the ability of gellan to resist influenza virus (H3N2) in a Transwell-24 well plate.

[0080] Materials • Influenza A virus H3N2 (NIDBVI00065) • MDCK cells • Culture medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA + 1mM sodium pyruvate + 1x PS +10% FBS • Working medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA + 1mM sodium pyruvate + 1μg / mL Trypsin +10% FBS • Anti-Influenza A virus Nucleoprotein antibody (GTX00858) • Secondary antibody Goat anti-Mouse IgG (H+L), Superclonal™ Recombinant Secondary Antibody, Alexa Fluor™ 488 (Invitrogen #A28175) • Millicell Hanging Cell Culture Insert, PET 1 μm, 24- well, (Millipore #PTRP24H48) • Test sample: Gellan (0.6% w / v) in 5% PBS

[0081] Procedure

[0082] The same procedure as for Example 2 was followed.

[0083] Results

[0084] The results of the H3N2 Transwell infection assay with gellan are shown in Figure 5 and demonstrate that gellan gum exhibits anti-influenza virus activity in MDCK cells.MDCK cells were infected with the H3N2 virus (MOI=5) in a Transwell-24 well plate for 48 hours with (n=2) or without (n=1) gellan gum treatment. The infected cells were stained with Influenza A virus nucleoprotein antibody (green), and the nuclei were stained with DAPI dye (blue). Representative images were shown at 200X magnification. Infected cells showed high infection levels in the absence of gellan gum treatment. However, with gellan gum treatment (a layer placed in the insert), virus nucleoprotein levels were significantly reduced.

[0085] Example 4 – antiviral properties: gellan

[0086] Tests were performed to assess the ability of gellan to inhibit Respiratory Syncytial Virus (RSV) infection in a Transwell-24 well plate.

[0087] Materials • Respiratory Syncytial Virus Long strain (NIDBVI00013) • HEp-2 cells • Culture medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA + 1mM sodium pyruvate + 1x PS +10% FBS • Working medium: MEM (Hyclone SH30024, With 2.0mM L- Glutamine) + NEAA + 1mM sodium pyruvate + 10% FBS • Anti-RSV antibody (ab20745) • Secondary antibody Donkey anti-Goat IgG (H+L), Cross- Adsorbed Secondary Antibody, Alexa Fluor™ 488 (Invitrogen #A11055) • Millicell Hanging Cell Culture Insert, PET 1 μm, 24- well, (Millipore #PTRP24H48) • Test sample: Gellan (0.6% w / v) in 5% PBS

[0088] Procedure

[0089] The same procedure as for Example 2 was followed, but with the HEep-2 cells used in step 1, the Anti-RSV antibody (1:400) used in step 11, and the Donkey anti-Goat secondary antibody used in step 13.

[0090] Results

[0091] The results of the RSV Transwell infection assay with gellan are shown in Figures 6a and 6b. HEp2 cells were infected with RSV virus in a Transwell-24 well plate for 48 hours with different multiplicity of infection (MOI). The infected cells were stained with RSV antibody (green), and the nuclei were stained with DAPI dye (blue). The representative images are shown (200X) in Figure 6a. Figure 6b shows that gellan gum exhibits anti-RSV activity in HEp2 cells. HEp2 cells were infected with the RSV (MOI=5) in a Transwell-24 well plate for 48 hours with (n=2) or without (n=1) the gellan gum. The infected cells were stained with RSV antibody (green), and the nuclei were stained with DAPI dye (blue). Representative images are shown at 200X magnification. Where cells were infected, high levels of infection was observed in the absence of the gellan gum treatment. Where there was a gellan gum treatment (a layer of gellan gum placed in the insert), no infection was observed. In conclusion, the results indicate that MOI = 5 and MOI = 10 yield better infection rates in the Transwell- 24 well plate. and show that no RSV infection was observed with gellan gum treatment when HEp-2 cells were challenged for 48 hours, and that the gellan gum layer blocked RSV diffusion and prevented infection during this period.

[0092] Example 5 – particle-trapping properties: NoriZite™ and gellan

[0093] Tests were performed to assess the ability of NoriZite™ and gellan to trap molecules and particles of different sizes, and thus act as barrier materials against a range of allergens.

[0094] Materials

[0095] Three dyes having different sizes (molecular through to particulate) were selected for testing: Rhodamine 6G (small molecule), Dextran blue (medium chained molecule) and Black ink (particulate, Parker). Other materials used in the tests are deionized water, gelatin (porcine), and sodium chloride. Figure 7a shows images of structures for the different dyes: (i) molecular structure of rhodamine, (ii) molecular structure for dextran blue (Mw used was 40 kDa), and (iii) optical micrograph of black ink showing the particulate nature (scale bar represents 100 ^^m). Figure 8 shows the particle sizing data for the ink particles: (a) particle size distribution for black ink with a linear x- axis, showing bi-modal distributions; (b) particle size distribution for black ink with a logarithmic x-axis, more easily showing smaller particle sizes (right hand vertical dotted lines show the mean (D50) particle size and left hand dotted lines denote P2.5 cut off), and (c) table of data for particle sizing. The Figure 8 data quantify the size of the particles in the ink used, and that the ink is made of particles that can be described as bimodal (2 distributions of particles centred around 2 and 8.5 µm, respectively). The P2.5 value refers to particles less than 2.5 µm, and can be used to show that the barrier materials are effective against p2.5 particles.

[0096] The barrier properties of NoriZite™ and gellan were tested by the following procedure:1) Prepare a gelatine sol (5% w / v) with 20 mM NaCl. 2) Cast the gelatine (200 µL) into the wells of a 48 well plate. 3) Allow the gelatine to cool (gel) and add the test material (200 µL) by spraying into the “treated” wells. 4) Undertake permeation kinetics study by adding the dye (200 µL) to the study wells. Add in reverse order (60 min to 1 min) so that all wells can be terminated at the same time. 5) Quench the study by washing all wells with deionized water, to remove excess dye and residual test material. 6) Analyse the wells using a plate reader by an absorbance scan (400 to 700 nm)

[0097] Figure 7b shows absorbance data collected using UV / Vis spectroscopy for permeation studies using NoriZite™ for (i) rhodamine, (ii) dextran blue, and (iii) black ink. Figure 7c shows absorbance data collected using UV / Vis spectroscopy for permeation studies using gellan for (i) rhodamine, and (ii) black ink. Note changes in axis. (“Spray” refers to results obtained with the NoriZite™ and gellan barrier materials in place, “no spray” refers to the results obtained without the NoriZite™ and gellan barrier materials in place).

[0098] Rhodamine is a very small molecule (480 g / mol), dextran blue has a long sugar chain which makes it ca. 40 kDa in size, and the ink is particulate (D50ca. 5 microns). It would be expected that the rhodamine should readily penetrate, based on size, followed by dextran blue and then the ink. It was found that the materials were capable of acting as a barrier for all dyes (Fig 7b), suggesting an ability to be effective for sizes ranging from nano to micron upwards. Moreover, these plots allow a direct comparison ofthe absorbance readings (not normalised data) (b+c). A comparison of the plots shows that the gellan was able to perform to an equal level with the NoriZite™ formulation with exception of the 1 hr rhodamine, where the gellan only performed slightly worse.

[0099] Particle trapping ability - NoriZite™

[0100] The results of the NoriZite™ tests are shown in more detail in Figure 9. Thus, Figure 9(a)(i) is an image of the washed plate following the end of the permeation experiment for rhodamine, and Figure 9(a)(ii) is the relative absorbance at ^^^^௫(528 nm) for the rhodamine dye as determined using UV / vis spectroscopy. Figure 9(b)(i) is an image of the washed plate following the end of the permeation experiment for black ink, and (ii) is the relative absorbance at ^^^^௫(592 nm) for the black ink as determined using UV / vis spectroscopy.

[0101] The amount of colour within each well is indicative of the amount of dye molecules (rhodamine) or particles (ink) which managed to penetrate into the gelatine gel (mimicking nasal tissue). In all cases, the addition of the spray prevented penetration (photos (a)(i) + (b)(i)). This was quantified (using standards - known quantities of the dyes) using UV / Vis (a technique that measures the amounts of light absorbed by materials – in this case rhodamine and ink) and has been plotted as a function of the exposure time. This data was normalised to be able to compare the different dyes ((a)(ii)+(b)(ii)) and shows that in the presence of the NoriZite™ spray (open markers), very little dye penetrated through to the gelatine, suggesting a large barrier effect.

[0102] Particle trapping ability - gellan

[0103] The results of the gellan tests are shown in more detail in Figure 10. Thus, Figure 10(a)(i) is an image of the washed plate following the end of the permeation experiment for rhodamine, and Figure 10(a)(ii) is the relative absorbance at ^^^^௫(528 nm) for the rhodamine dye as determined using UV / vis spectroscopy. Figure 10(b)(i) is an image of the washed plate following the end of the permeation experiment for black ink, and Figure 10(b)(ii) is the relative absorbance at ^^^^௫(592 nm) for the black ink as determined using UV / vis spectroscopy.

[0104] The amount of colour within each well is indicative of the amount of dye molecules (rhodamine) or particles (ink) which managed to penetrate into the gelatine gel (mimicking nasal tissue). In all cases, the addition of the spray prevented penetration (photos (a)(i) + (b)(i)). This was quantified (using standards - known quantities of the dyes) using UV / Vis (a technique that measures the amounts of light absorbed by materials – in this case rhodamine and ink) and has been plotted as a function of the exposure time. This data was normalised to be able to compare the different dyes ((a)(ii)+(b)(ii)) and shows that in the presence of the NoriZite™ spray (open markers), very little dye penetrated through to the gelatine, suggesting a large barrier effect.

[0105] Comparison of particle trapping ability - NoriZite™ and gellan

[0106] Figure 11 shows a comparison of the adsorption spectra for NoriZite™ and gellan barrier materials. The plots show the percentage difference in absorption spectra (no spray minus spray), i.e, reduction in permeation, for: (a) the NoriZite™ formulation, and (b) gellan only. Note changes in axis.The absorbance data are interpreted as the differencein the amount dye which managed to get into the gelatine in the presence and absence of the spray layer, thus showing the effectiveness of the spray as a barrier. At low time points the difference is lower, as the amount which could permeate into the gelatine in this time (without the barrier) is less. Across all times there was a reduction in the amount of permeation (as shown by positive numbers throughout) showing that at longer timeframes up to ca. 90% reduction in the amount of dye entering the gelatine was achieved. The effectiveness of the barrier function is comparable for NoriZite™ and gellan only, apart from the 60 min rhodamine.

[0107] Example 6 - NoriZite™ pollen permeation assay

[0108] The ability of NoriZite™ to trap pollen (at 24 hrs) was tested using the same Transwell setup as the virology studies described in Examples 2 to 4.

[0109] The results of the study are shown in Figure 12, which plots absorbance as measured by UV / Vis spectroscopy for the permeation of pollen through NoriZite™ formulation using the Transwell setup. Inserts show images of individual wells. Negative control was water only. In this test, NoriZite™ spray was placed in a basket with the pollen (in solution) above it. This was left for 24 hours under static conditions, and the basket removed. The amount of pollen which had managed to get through the spray and into the well underneath was measured (Figure 12). The absorbance can be directly correlated to the amount of pollen which managed to get through. The pollen control is the same system as is used for the 2 sprays. The results show that the spray managed to completely prevent the movement of the pollen into the lower well, which was still achieved in the absence of spray.

[0110] It will be appreciated that the specific embodiments described herein are for illustrative purposes only, and that further modifications and variations of the embodiments are possible without departing from the scope ofthe present invention as defined by the appended claims.

Claims

CLAIMS 1. A sprayable formulation for use in reducing or preventing viral infections and / or allergic reactions, wherein the formulation comprises a barrier-forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material comprises a naturally non-sulphated polysaccharide or derivative thereof, and the formulation does not comprise any additional materials which exhibit antiviral or antiallergy activity.

2. A sprayable formulation for use in reducing or preventing viral infections and / or allergic reactions, wherein the formulation comprises a barrier-forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material comprises a naturally non-sulphated polysaccharide or derivative thereof, and the formulation does not comprise carrageenan.

3. A sprayable formulation for use in reducing or preventing viral infections and / or allergic reactions, wherein the formulation comprises a barrier-forming material for forming a physical barrier with a mucosal membrane or ocular barrier against infection by and / or transmission of viruses and / or allergens, wherein the barrier-forming material substantially consists of a naturally non-sulphated polysaccharide or derivative thereof.

4. A formulation according to claim 1, 2 or 3 for use as an oral, nasal or ocular spray.

5. A formulation according to any preceding claim for use in the prevention of infection and / or transmission of airborne viruses.

6. A formulation according to claim 5 wherein the virus is selected from one or more of influenza-, rhino-, adeno-, entero-, Respiratory Syncytial Virus and a coronavirus.

7. A formulation according to any preceding claim for use in the prevention of allergic reactions through the prevention of infection by and / or transmission of an airborne allergen.

8. A formulation according to claim 7 wherein the allergic reaction is associated with allergic rhinitis and / or hayfever.

9. A formulation according to any preceding claim which has an inherent half-life on mucosa of 3 to 5 hours.

10. A formulation according to any preceding claim which remains detectable for 6 hours or longer following initial application to mucosa.

11. A formulation according to any preceding claim which has a dynamic viscosity of 0.05 to 100 Pa.s at 25 °C.

12. A formulation according to any preceding claim wherein the non-sulphated polysaccharide or derivative thereof is selected from the group consisting of gellan, dextran, alginate, pectin, xanthan, xylitol and mixtures thereof.

13. A formulation according to claim 12 wherein thenon-sulphated polysaccharide or derivative thereof comprises gellan.

14. A formulation according to any preceding claim which further comprises a diluent.

15. A formulation according to claim 14 wherein the diluent is a saline solution.

16. A formulation according to any preceding claim wherein the concentration of non-sulphated polysaccharide or derivative thereof in the formulation is from 0.1 to 2.0% w / v.

17. A formulation according to any preceding claim which further comprises a dispersing agent.

18. A formulation according to any preceding claim which comprises hyaluronic acid and / or xylitol and / or aloe vera.

19. A formulation according to claim 18 which comprises or consists of gellan and xylitol, gellan and hyaluronic acid, or gellan and aloe vera, or gellan and a combination of xylitol, hyaluronic acid and / or aloe vera.

20. A formulation according to claim 2 or any one of claims 4 to 19 when dependent upon claim 2 which comprises fucoidan.

21. A formulation according to claim 20 which comprises or consists of gellan and fucoidan.

22. A spray device comprising the formulation of any preceding claim, a body for containing the formulation therein, and a nozzle for spraying the formulation.

23. A spray device according to claim 22 which is anasal spray device.

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