Hydroxyapatite composition for the treatment and / or prevention of viral infections

Abstract

The present invention relates to a composition comprising hydroxyapatite for use in the treatment and / or prevention of viral infections.

Description

Technical Field

[0001] This invention relates to a composition containing 0.001 to 40 wt.% hydroxyapatite for the treatment and / or prevention of viral infections. Background Technology

[0002] Viruses belonging to the family Coronaviridae were first characterized in the 1960s. Infections with viruses of this family are common in all mammals, including humans. The SARS-CoV-2 outbreak demonstrated the need for novel drug compositions to treat and prevent widespread viral infections, particularly SARS-CoV-2 infection.

[0003] Coronaviruses are RNA viruses with linear ss-RNA (single-stranded RNA) that spread through droplet infection, causing fever and respiratory problems. Several species are relatively harmless, causing only acute and mild symptoms or producing an asymptomatic course (HCoV-OC43, 229E, HKU1, and HL63). On the other hand, SARS-CoV (Severe Acute Respiratory Syndrome Coronavirus), MERS-CoV (Middle East Respiratory Syndrome Coronavirus), and SARS-CoV-2 are coronaviruses that can cause severe respiratory and lung infections. To date, only very limited treatment or preventative measures exist besides exposure prophylaxis. Meister et al. (The Journal of Infectious Diseases 2020, 222, pp 1289-1292) have conducted in vitro studies on the anti-SARS-CoV-2 activity of several mouthwash compositions. Summary of the Invention

[0004] In view of the above, the object of the present invention is to provide a new, safe and effective composition for the treatment and / or prevention of general viral infections, particularly for the treatment and prevention of SARS-CoV-2 infection.

[0005] These objectives have surprisingly been achieved by compositions containing 0.001 to 40 wt.% hydroxyapatite.

[0006] Surprisingly, it was found that, based on the above aspects, infection with the virus can be prevented, or at least the probability of infection can be significantly reduced. Furthermore, based on the above aspects, the viral count in the respiratory tract is significantly reduced, thus the infected person is no longer infectious to third parties.

[0007] In another aspect, the present invention relates to a composition comprising:

[0008] 0.001 to 40 wt.% hydroxyapatite,

[0009] 0.001 to 20 wt.% of a water-soluble zinc salt, wherein the water-soluble zinc salt is selected from zinc L-pyrrolidone carboxylate, zinc acetate, zinc chloride, zinc histidine, zinc gluconate, zinc aspartate, zinc citrate, zinc sulfate, zinc lactate, and mixtures thereof.

[0010] 0.001 to 5 wt.% of anionic surfactants, and

[0011] 0.001 to 5 wt.% of polyols, said polyols being selected from erythritol, arabinitol, lactitol, maltitol, mannitol, sorbitol, xylitol and mixtures thereof.

[0012] The present invention also relates to a component kit comprising the composition of the present invention and a spray device, mouthwash device or gargling device for applying the composition to the mucous membranes of the nose, mouth (oral cavity) and / or throat (pharynx). Detailed Implementation

[0013] The following definitions are relevant to embodiments of the present invention.

[0014] The term “comprising” should be interpreted as encompassing all specifically mentioned features as well as optional, additional, and unspecified features, while the term “consisting of” includes only the specified features. Therefore, “comprising” includes the components specified by “consisting of” as a limitation.

[0015] Unless otherwise specified, the terms “weight-%” or “wt.-%” should be understood as referring to the weight of a component relative to the total weight of the corresponding composition.

[0016] The term "water-soluble" refers to zinc salts with a solubility of 0.1 g / L or greater under standard conditions. Conversely, the term "water-insoluble" refers to zinc salts with a solubility of less than 0.1 g / L under standard conditions, namely at a temperature of 15°C and a pH of 7.0.

[0017] The term "film-forming" polymer refers to a polymer that forms an adhesive, continuous layer when applied to a surface. In this invention, when the composition is locally applied to an adhesive membrane, the film-forming polymer results in the formation of an adhesive layer of the composition, which further enhances the adhesive properties to the adhesive membrane.

[0018] As used herein, on the one hand, the term "prevention" of viral infection (also known as preventative measures) refers to preventing (local) infection in a subject who has already been exposed to a virus. On the other hand, the term "prevention" also refers to preventing the transmission of infection to other subjects in the event that a subject using the composition is already infected with a virus. In other words, the composition generally effectively prevents viral infection and / or further transfer or distribution of the virus, for example, via aerosols / droplets. Thus, the compositions of the present invention achieve a dual approach to preventing the widespread transmission of viruses.

[0019] According to the present invention, the “treatment” and “prevention” of viral infection are based on the antiviral activity of the composition, thereby reducing the viral count (viral load) in the mouth, throat, and nasal regions (i.e., the upper respiratory tract), resulting in effective local treatment of the virus, as the virus is primarily located in these areas. It is believed that the composition of the present invention can effectively reduce the viral count, particularly in the throat, even before the virus is able to enter host cells and cause infection. Upon application, the composition of the present invention effectively reduces the viral count in the mouth, nose, and / or throat regions (i.e., the upper respiratory tract) by up to 99%, preferably up to 95%, more preferably up to 93%, such as up to 90%. Surprisingly, this efficacy has been found to last for more than 6 hours from the start of application of the composition, preferably 1 to 6 hours, more preferably 1 to 4 hours. In other words, the composition of the present invention effectively prevents viral infection for more than 6 hours, preferably up to 6 hours, at least 3 or 4 hours. Therefore, the composition allows for a continuous or sustained reduction in the viral count over a considerable period of time. At least during this period, the composition of the present invention effectively prevents (local) infection and also avoids transmission of infection to other subjects; that is, the composition effectively prevents viral infection and / or, particularly, further transfer or distribution of viruses transmitted via aerosols / droplets. Without wishing to be bound by theory, it is assumed that hydroxyapatite binds to viral RNA.

[0020] Preferred embodiments of the invention are defined below. These preferred embodiments may be individual or in combination. Furthermore, it should be understood that the following preferred embodiments relate to all aspects of the invention, namely, the use of compounds, and reagent kits for compounds and components.

[0021] In one embodiment, the present invention relates to a composition comprising 0.001 to 40 wt.% hydroxyapatite for the treatment and / or prevention of viral infections. In a preferred embodiment, the composition comprises 0.01 to 20 wt.% hydroxyapatite, 0.05 to 10 wt.% hydroxyapatite, or 0.1 to 5 wt.% hydroxyapatite.

[0022] The above composition is useful for both the treatment and prevention of viral infections. In a preferred embodiment, the composition is used for the prevention of viral infections.

[0023] Hydroxyapatite (HAP) is a naturally occurring inorganic mineral with the general formula Ca5(PO4)3(OH). In a preferred embodiment, hydroxyapatite is free of any ions, i.e., the amount of ions (Ca ions) in hydroxyapatite is less than 1 wt% 2+ PO4 3- and OH - It is replaced by different ions.

[0024] Hydroxyapatite is naturally occurring, but it can also be obtained by methods known to those skilled in the art. For example, hydroxyapatite can be obtained by reacting calcium salts such as CaCl2 or Ca(NO3)2 with phosphates such as (NH4)3PO4, Na3PO4, Na2HPO4, or NaH2PO4 in water at a temperature of 10 to 100°C or in an autoclave at a temperature above 100°C.

[0025] Hydroxyapatite can be doped with the following ions: CO3 2- Ag + Mg 2+ Cu 2+ Therefore, in non-limiting embodiments, the term "hydroxyapatite" should be understood to encompass compositions doped with the aforementioned ions and having the following formula:

[0026] Ca 10-x M x (PO4) 6-y (CO3) y+z (OH) 2-z ,

[0027] Where M is Cu, Mg, or Ag.

[0028] x is a number between 0 and 0.6.

[0029] y is a number between 0 and 0.9, and

[0030] z is a number between 0 and 0.32.

[0031] In a preferred embodiment, x is a number between 0.0055 and 0.6, y is a number between 0.065 and 0.9, and z is a number between 0 and 0.32.

[0032] In a preferred embodiment, hydroxyapatite is free of Ag. + .

[0033] This ion doping can be achieved by adding a suitable salt, such as MgCl2, during the formation of hydroxyapatite.

[0034] In one embodiment, the composition of the present invention is free of zinc hydroxyapatite, that is, the hydroxyapatite of the present invention does not contain zinc ions.

[0035] In a non-limiting embodiment, the volume-based particle size X of hydroxyapatite 50 The wavelength range is 1 to 1000 nm, 10 to 500 nm, 20 to 300 nm, 30 to 200 nm, or 50 to 150 nm, preferably 30 to 200 nm. According to DIN ISO 14887:2010, X 50 The value can be measured using laser diffraction with a Mastersizer 2000 (Malvern Instruments GmbH).

[0036] In a non-limiting embodiment, the hydroxyapatite has a hexagonal lattice with an a-axis length of 0.930 to 0.950 nm, preferably 0.933 to 0.948 nm, particularly preferably 0.936 to 0.945 nm, and a c-axis length of 0.680 to 0.700 nm, preferably 0.682 to 0.696 nm, particularly preferably 0.685 to 0.692 nm. The lattice parameters can be determined by X-ray powder diffraction and Rietveld analysis using a Bruker D8 diffractometer.

[0037] In one embodiment, the composition further comprises 0.001 to 20 wt.% of a water-soluble zinc salt selected from zinc L-pyrrolidone carboxylate (zinc PCA), zinc acetate, zinc chloride, zinc histidine, zinc gluconate, zinc aspartate, zinc citrate, zinc sulfate, zinc lactate, and mixtures thereof.

[0038] The presence of additional zinc ions has been found to further enhance the antiviral activity of the present invention. Zinc PCA is particularly effective and preferred.

[0039] Water-soluble zinc salts also include solvates (such as hydrates) of the corresponding zinc salts. Preferably, the composition contains water. Therefore, the specific solvate used is not particularly relevant.

[0040] In a preferred embodiment, the composition comprises 0.01 to 10 wt.%, 0.05 to 5 wt.%, or 0.05 to 1 wt.%, preferably 0.05 to 0.5 wt.%, of a water-soluble zinc salt. Containing a water-soluble zinc salt within these ranges, preferably zinc PCA, the compositions of the present invention are unexpectedly remarkably effective in treating and / or preventing viral infections.

[0041] In one embodiment, the composition of the present invention further comprises 0.001 to 5 wt.% of a surfactant, preferably anionic, more preferably 0.001 to 1 wt.% of a surfactant, preferably anionic surfactant. Surprisingly, the composition of the present invention has been found to be effective against viruses, even when using small amounts of anionic surfactant, such as 0.001 to 1 wt.%, more preferably 0.01 to 0.9 wt.%, or even more preferably any of the following ranges: 0.05 to 0.8 wt.%, 0.1 to 0.7 wt.%, 0.15 to 0.60 wt.%, 0.20 to 0.50 wt.%, 0.25 to 0.45 wt.%. Surprisingly, the composition has been found to be effective even with such low total amounts of anionic surfactant. It is believed that the anionic surfactant works synergistically with hydroxyapatite.

[0042] Without being bound by theory, it is assumed that when the composition contains the anionic surfactant of the present invention, the surfactant effectively disrupts and / or deactivates and / or dissolves the outermost protective layer (viral envelope) of the enveloped virus. In other words, the composition effectively disrupts the integrity of the viral envelope. In general, the compositions of the present invention provide highly effective strategies for the treatment and / or prevention of viral infections, particularly against enveloped viral infections such as SARS-CoV-2 infection.

[0043] In one embodiment, the present invention relates to a composition comprising at least two different anionic surfactants A and B in a weight ratio of 20 / 1 to 1.1 / 1, wherein surfactant A is an alkyl sulfate and surfactant B is selected from alkyl sulfates, alkyl sarcosinates and alkyl taurates, wherein the total amount of anionic surfactants in the composition is 1 wt.% or less.

[0044] In one embodiment, the composition further comprises an anionic surfactant C (different from surfactants A and B, respectively), selected from alkyl sulfates, alkyl sarcosinates, and alkyl taurates. In other words, the compositions of the present invention preferably comprise at least (preferably precisely) three different anionic surfactants A, B, and C, wherein surfactant A is an alkyl sulfate, surfactants B and C are selected from alkyl sulfates, alkyl sarcosinates, and alkyl taurates, more preferably surfactants B and C are selected from alkyl sarcosinates and alkyl taurates, and even more preferably surfactant B is an alkyl taurate and surfactant C is an alkyl sarcosinate. Preferably, the weight ratio A / C is from 16 / 1 to 1.1 / 1. According to the present invention, anionic surfactants A, B, and C are alkyl sulfates, alkyl sarcosinates, alkyl taurates, and mixtures thereof.

[0045] In a preferred embodiment, the surfactant is selected from alkyl sulfates, alkyl sarcosinates, alkyl taurates, and mixtures thereof. Those skilled in the art will understand that the above terms refer to charge-neutral compounds containing an antication M, such as sodium.

[0046] Alkyl sulfates have the formula ROSO3M, alkyl sarcosinates have the formula RC(O)N(CH3)CH2CO2M, and alkyl taurine salts have the formula RC(O)N(CH3)CH2CH2SO3M, where R is C4-C. 26 Alkyl or C4-C 26 The compound is alkenyl, and M is a water-soluble cation, such as ammonium, sodium, potassium, or triethanolamine. Preferably, R is C. 12 -C 16 Alkyl or C 12 -C 18 Alkenyl group.

[0047] According to the present invention, the anionic surfactant in the composition is preferably: sodium dodecyl sulfate as surfactant A, sodium methyl cocoyl taurate as surface surfactant B, and sodium myristoyl sarcosinate as surface activator C. While other anionic surfactants may be present, it is most preferably the composition does not contain any other anionic surface activators.

[0048] Preferably, the weight ratio (A / B ratio) of surfactant A to surfactant B, as specified herein, is from 19 / 1 to 1.1 / 1, 18 / 1 to 1.1 / 1, or 17 / 1 to 1.1 / 1. In a particularly preferred embodiment, the weight ratio A / B is from 16 / 1 to 1.5 / 1, more preferably from 15 / 1 to 2 / 1. Within these ranges, the compositions of the present invention are surprisingly effective in treating and / or preventing viral infections.

[0049] Even more preferably, as described herein, the weight ratio (A / C) of surfactant A to surfactant C (if contained) is 27 / 1 to 1.1 / 1, 26 / 1 to 1.1 / 1, 25 / 1 to 1.1 / 1, 20 / 1 to 1.1 / 1, 16 / 1 to 1.1 / 1, 15 / 1 to 1.1 / 1, or 14 / 1 to 1.1 / 1. In a particularly preferred embodiment, the weight ratio A / C is 13 / 1 to 2 / 1, more preferably 12 / 1 to 5 / 1, even more preferably 11 / 1 to 8 / 1, and most preferably about 10 / 1. Within these ranges, the compositions of the present invention are surprisingly effective in treating and / or preventing viral infections.

[0050] In a particularly effective embodiment, the weight ratio (ratio A / B / C) of all three surfactants A, B and C is preferably about 70 / 9 / 5.

[0051] Surfactant A, i.e., alkyl sulfate, preferably sodium dodecyl sulfate, is preferably contained in the composition in the range of 0.001 to 1.8 wt.-%, more preferably 0.01 to 1.5 wt.-%, even more preferably 0.1 to 0.9 wt.-%, and most preferably 0.5 to 0.8 wt.-%.

[0052] Surfactant B, i.e., alkyl sulfate, alkyl sarcosinate or alkyl taurate, preferably alkyl sarcosinate or alkyl taurate, most preferably sodium methyl cocoyl taurate, is preferably contained in the composition in the range of 0.001 to 0.5 wt.-%, more preferably 0.01 to 0.4 wt.-%, even more preferably 0.05 to 0.3 wt.-%, and most preferably 0.07 to 0.2 wt.-%.

[0053] Surfactant C, i.e., alkyl sulfate, alkyl sarcosinate or alkyl taurate, preferably alkyl sarcosinate or alkyl taurate, most preferably sodium myristoyl sarcosinate, is preferably contained in the composition in the range of 0.001 to 0.5 wt.-%, more preferably 0.01 to 0.1 wt.-%, even more preferably 0.02 to 0.08 wt.-%, and most preferably 0.03 to 0.06 wt.-%.

[0054] According to the present invention, the most preferred anionic surfactant mixture comprises or consists of: 0.5 to 0.8 wt.% sodium dodecyl sulfate as surfactant A, 0.07 to 0.2 wt.% sodium methyl cocoyl taurate as surface surfactant B, and 0.03 to 0.06 wt.% sodium myristoyl sarcosinate as surface activator C.

[0055] In another preferred embodiment of the invention, the composition contains only one anionic surfactant, i.e., only an alkyl sulfate, such as sodium dodecyl sulfate (SDS). In a preferred embodiment, the composition contains approximately 0.001 to 1 wt.-%, more preferably 0.01 to 0.5 wt.-%, of sodium dodecyl sulfate and contains no other anionic surfactants. Such a composition remains effective in treating and / or preventing viral infections. However, compared to compositions containing a combination of at least two anionic surfactants A and B (and optionally C), this composition is slightly less effective and foams more vigorously upon application, making the overall foaming behavior less convenient for the patient. This alternative composition of the invention is also applied topically to the mucous membranes of the (upper) respiratory tract, including the nose, mouth (oral cavity), and / or throat (pharynx). All further additional features and limitations described herein are also valid and applicable to this alternative embodiment.

[0056] In a particularly preferred embodiment, the composition comprises 0.001 to 1 wt.% of a surfactant selected from alkyl sulfates, alkyl sarcosinates, alkyl taurates, and mixtures thereof.

[0057] In a preferred embodiment, the composition comprises 0.001 to 1 wt.% sodium dodecyl sulfate. In a preferred embodiment, the composition comprises 0.001 to 1 wt.% sodium myristoyl sarcosinate. In a preferred embodiment, the composition comprises 0.001 to 1 wt.% sodium methylcocoyl taurate. In a preferred embodiment, the composition comprises 0.001 to 1 wt.% sodium dodecyl sulfate, 0.001 to 1 wt.% sodium myristoyl sarcosinate, and 0.001 to 1 wt.% sodium methylcocoyl taurate. In an even more preferred embodiment, the composition comprises 0.001 to 1 wt.% of a surfactant selected from sodium dodecyl sulfate, sodium myristoyl sarcosinate, sodium methylcocoyl taurate, and mixtures thereof.

[0058] In one embodiment, the composition further comprises a surfactant selected from nonionic, cationic, or amphoteric surfactants. It is also possible that the composition comprises other anionic surfactants in addition to surfactants A, B, and C described herein. Suitable surfactants are described in "Cosmetic Formulation of Skin Care Products," Draelos et al., Taylor & Francis Group, 2006.

[0059] Suitable nonionic surfactants are selected from polyoxyethylene fatty acid ethers, polyglycerol ethers of fatty acids, polyglycerol esters of fatty acids, and C4-C... 26 Fatty alcohol ethoxylates, alkylphenol ethoxylates, ethoxylated amines / amides, glycerol C4-C 26 Fatty acid amides, glycerol C4-C 26 Fatty acid esters, sorbitan fatty acid esters, and mixtures thereof. Prefix "C" x -C y "" indicates the number of carbon atoms in each functional group. C4-C 26Non-limiting examples of fatty alcohol ethoxylates include pentaethylene glycol monododecyl ether (also known as C12E5), hexaethylene glycol monododecyl ether (C12E6), heptaethylene glycol monododecyl ether (C12E7), and octaethylene glycol monodecyl ether (C12E8). Non-limiting examples of alkylphenol ethoxylates include Triton. (octylphenol ethoxylate) and Nonidet (4-Nonylphenol ethoxylate). Non-limiting examples of ethoxylated amines / amides include polyethoxylated tallow amine, cocamide monoethanolamine, and cocamide diethanolamine. Glycerol C4-C 26 Non-limiting examples of fatty acid esters are glyceryl monostearate and glyceryl monolaurate. Non-limiting examples of sorbitol fatty acid esters are sorbitol monolaurate, sorbitol monostearate, and sorbitol tristearate.

[0060] Other anionic surfactants available in this article include those with the formula RO(C2H4O). x alkyl ether sulfates of SO3M, where R is C4-C 26 Alkyl or C4-C 26 The alkyl ether sulfate is an alkenyl group, x is 1 to 10, and M is a water-soluble cation such as ammonium, sodium, potassium, and triethanolamine. The alkyl ether sulfates available in this invention are condensation products of ethylene oxide and a monohydric alcohol having about 4 to about 26 carbon atoms. Preferably, in the alkyl ether sulfate, R is C 14 -C 16 Alkyl or C 14 -C 18Alkenyl alcohols can be derived from fats, such as coconut oil or animal fats, or they can be synthetic. Laureth alcohol and straight-chain alcohols derived from coconut oil are preferred herein. Such alcohols are reacted with ethylene oxide in a ratio of 1 to 10, particularly 3 moles, to obtain a mixture of molecular types (having, for example, an average of 3 moles of ethylene oxide per mole of alcohol) which is then sulfated and neutralized. Specific examples of the alkyl ether sulfates of the present invention are coconut alkyl trioxyethylene sulfate; lithium tallow alkyl trioxyethylene sulfate; sodium tallow alkyl hexaoxyethylene sulfate; and sodium dodecyl ether sulfate. Other examples of anionic surfactants within the scope of the terminology of the present invention are: reaction products of fatty acids esterified with isethionic acid and neutralized with sodium hydroxide, wherein, for example, the fatty acid is derived from coconut oil; sodium or potassium salts of fatty acid amides of methyl tauride, wherein the fatty acid is derived, for example, from coconut oil. Other anionic surfactants are amino acid surfactants containing alkyl glutamate salts, such as sodium cocoyl glutamate / disodium cocoyl glutamate, alkyl glycinate salts, alkyl alanine salts such as sodium cocoyl alanine, and mixtures thereof.

[0061] Cationic surfactants include primary amines, secondary amines, tertiary amines, such as ostinidine dihydrochloride, and quaternary ammonium salts, such as cetrimonium bromid, cetlypyridinium chloride, benzalkonium chloride, benzyl chloride, dimethyldioctadecylammonium chloride, and dioctadecyldimethylammonium bromide.

[0062] Amphoteric surfactants have both anionic and cationic functional groups. Examples of amphoteric surfactants are derivatives of aliphatic secondary and tertiary amines, wherein the aliphatic groups can be straight-chain or branched, and one of the aliphatic substituents contains about 8 to about 18 carbon atoms, and the other contains an anionic solubilizing group, such as a carboxyl group, sulfonate, sulfate, phosphate, or phosphonate. Specific examples of amphoteric surfactants are sodium 3-dodecylaminopropionate, sodium 3-dodecylaminopropanesulfonate, and N-alkylaminoethanesulfonates such as those prepared by reacting dodecylamine with sodium hydroxyethylsulfonate. Particularly preferred amphoteric surfactants are betaines, such as, for example, cocamidopropyl betaine. Based on the weight of the composition, the amphoteric surfactant component may be present in the composition in an amount ranging from about 5 to about 15 wt.-%, preferably from about 9 to about 12 wt.-%.

[0063] Preferably, the total amount of all surfactants contained in the composition of the present invention is 15 wt.% or less, more preferably 10 wt.% or less, more preferably 5 wt.% or less, and most preferably 1 wt.% or less. It is also preferred that the composition of the present invention contains no other surfactants except for anionic surfactants, particularly except for anionic surfactants A, B, and C described herein, and especially no nonionic, cationic, and / or amphoteric surfactants. Surprisingly, the composition has been found to be effective even with such a low total amount of surfactants.

[0064] In one embodiment, the composition comprises 0.001 to 5 wt.% of a polyol selected from erythritol, arabinitol, lactitol, maltitol, mannitol, sorbitol, xylitol, and mixtures thereof. Polyols can act as flavoring agents, particularly as sweeteners, or as masking agents to minimize or prevent tooth decay while masking otherwise unpleasant tastes. Therefore, the use of polyols, such as xylitol, has the additional effect that tooth decay caused by caries is minimized and / or prevented because cariogenic bacteria of the Streptococcus mutans family cannot metabolize polyols. Preferably, the composition includes sorbitol and / or xylitol.

[0065] The composition may contain 0.001 to 60 wt.% ethanol. In an alternative embodiment, the composition of the present invention does not contain ethanol. Ethanol has disinfectant and antiviral properties. Prior art mouthwashes and spray compositions considered effective as antiviral compositions contain ethanol. It is evident, according to Meister et al. (The Journal of Infectious Diseases, 2020, 222, pp. 1289-1292), that only those compositions containing ethanol exhibit in vitro activity against SARS-CoV-2. In view of this, it is surprising that the compositions of the present invention are effective in treating and preventing viral infections, particularly coronavirus infections, even in the absence of ethanol. Therefore, it is surprising that the compositions of the present invention, even without ethanol, remain effective antiviral compositions.

[0066] The composition may additionally include flavoring agents. Non-limiting examples of flavoring agents are sweeteners and essential oils. Sweeteners may be polyols, aspartame, saccharin, and corn syrup. Non-limiting examples of essential oils include menthol, peppermint oil, and spearmint oil. In one embodiment, the composition contains 0.001 to 5 wt.% of an essential oil selected from eucalyptol, thymol, menthol, anise oil, fennel oil, and levonorgestrel. These essential oils may possess additional beneficial properties and act as antiviral and antipuritic agents.

[0067] In one embodiment, the composition comprises transferrin, preferably lactoferrin. These proteins can further enhance the antiviral properties of the compositions of the present invention.

[0068] In one embodiment, the composition comprises a film-forming polymer selected from carrageenan, carboxymethyl cellulose (CMC) and pharmaceutically acceptable salts thereof, hydroxypropyl methyl cellulose (HPMC), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid and pharmaceutically acceptable salts thereof, copolymers of methyl vinyl ether and maleic acid and pharmaceutically acceptable salts thereof, carboxymethyl chitin, polyvinylpyrrolidone, chitosan, and mixtures thereof.

[0069] Non-limiting examples of pharmaceutically acceptable salts include salts containing calcium, sodium, potassium, and mixtures thereof. Pharmaceutically acceptable salts of hyaluronic acid include earth metal salts, such as sodium and potassium salts.

[0070] It is believed that the invention also works by forming a protective layer of the composition of the invention on the mucous membranes of the mouth, throat, and / or nose (i.e., the upper respiratory tract). This antiviral protective layer effectively prevents uninfected subjects from contracting the virus via droplet transmission. Furthermore, the composition reduces the viral count in the respiratory tract, and the formation of the protective layer reduces the infectivity of already infected subjects to other subjects, thereby also preventing further infection.

[0071] Furthermore, the film-forming polymer increases the contact time between hydroxyapatite and the mucous membranes in the mouth and / or nose by forming a stable and durable active layer of hydroxyapatite on the mucous membrane.

[0072] The copolymer of polyvinyl ether and maleic acid is preferably an alternating copolymer. It should be understood that the polymer is derived from monomer units of methyl vinyl ether and maleic acid or maleic anhydride, and the copolymer is also referred to as poly(methyl vinyl ether-co-maleic acid). This polymer can be obtained, for example, by free radical polymerization of monomer units, and the copolymer of methyl vinyl ether and maleic acid can be used as a Gantrez copolymer. TM S polymer (International Nomenclature for Cosmetic Ingredients: PVM / MA copolymer; Ashland Inc.) is commercially available.

[0073] Pharmaceutically acceptable salts of the copolymer can be alkali metals and / or alkaline earth metals. Therefore, these salts can be selected from lithium, sodium, potassium, magnesium, calcium, and mixtures thereof. Preferably, the salt is a sodium / calcium salt. A calcium-sodium copolymer of poly(methyl vinyl ether-co-maleic acid) can be used as a Gantrez... TM MS-955 polymer (International Nomenclature for Cosmetic Ingredients: Calcium / Sodium PVM / MA Copolymer, Ashland Inc.) is commercially available.

[0074] In one embodiment, the composition comprises 0.01 to 10 wt.-%, 0.1 to 5 wt.-%, or 1 to 2 wt.-%, preferably 0.5 to 3 wt.-%, of a film-forming polymer.

[0075] In one embodiment, the composition further comprises a water-insoluble zinc salt. In one embodiment, the water-insoluble salt is present in an amount of 0.001 to 20 wt.%. In a preferred embodiment, the composition comprises 0.01 to 10 wt.%, 0.05 to 5 wt.%, or 0.05 to 1 wt.%, preferably 0.05 to 0.5 wt.%. Containing water-insoluble zinc salts within these ranges, the compositions of the present invention are surprisingly effective in treating and / or preventing viral infections.

[0076] In another embodiment, the water-insoluble zinc salt is zinc oxide.

[0077] In one embodiment, the composition further comprises additional active ingredients selected from menthol, lactoferrin, sorbitol, xylitol, saccharin, and mixtures thereof. These ingredients may have anti-inflammatory and / or skin-protective properties, and further enhance the treatment and / or prevention of viral infections. These additional active ingredients are preferably present in amounts of 0.001 to 10 wt.%, 0.01 to 5 wt.%, or 0.05 to 2 wt.%.

[0078] In another embodiment, the composition may contain preservatives such as benzoic acid, phenoxyethanol, citric acid, lactic acid, ascorbic acid, tocopherol, and pharmaceutically acceptable salts thereof.

[0079] In one embodiment, the composition is a liquid topical composition, such as a cosmetic, medical, or pharmaceutical composition.

[0080] All compositions of the present invention described herein are preferably applied topically to the mucous membranes of the (upper) respiratory tract (including the nose, mouth (oral cavity), and / or throat (pharynx)). Most preferably, the compositions of the present invention are applied topically to the throat (pharynx), such as by gargling or any other type of dispensing or application. Preferably, they are applied topically to the mucous membranes as mouthwash or as aerosols sprayed, preferably as mouthwash. Mouthwashes suitable according to the present invention are mouthwashes applied by rinsing / brushing the mouth, nose, and / or throat, for example by gargling. They are also named mouthwashes or oral rinsing solutions (suitable for rinsing and / or gargling). Application as mouthwash or spray / aerosol has the further advantage of forming a uniform, homogeneous, and durable protective layer on the mucous membranes. Furthermore, protection can be achieved over large areas, thus achieving better protection.

[0081] A spray device can be used to apply a composition to the mucous membranes of the mouth (oral cavity), throat (pharynx), or nose. Preferably, the composition is applied to the mucous membranes of the mouth or pharynx using a spray device. Particularly preferred is that the spray device includes a tool for (pre)determining the amount of composition to be applied.

[0082] Suitable pump-type spray devices are known (see US 4245967) and are commercially available as “throat sprays.” These sprays are typically used to treat sore throat caused by bacterial infection of the throat and mucous membranes and / or to reduce any symptoms of such infection. These sprays may contain antibacterial ingredients to combat the bacterial infection, as well as analgesics to reduce any symptoms of pain and / or soreness.

[0083] Spraying devices typically include an inlet chamber and an outlet through which the composition is sprayed in a predetermined amount via a suitable tool for ejecting the composition through a nozzle. Preferably, the spraying device is a pump-type spraying device. Such a pump-type sprayer includes atomizing nozzles that disperse the liquid composition as a fine aerosol. This aerosol covers the sprayed area and forms a thin film.

[0084] The compositions of the present invention described herein are preferably applied several times daily, such as 1 to 5 times, more preferably 2 to 4 times, and most preferably about 2 to 3 times, particularly before and / or after contact with a subject (potentially) with a virus and / or a virus-infected individual. When used as a mouthwash, the composition is preferably applied by gargling (rinsing the mouth, especially the throat / pharynx). A suitable volume to be applied is 5 to 25 ml per application, preferably 10 to 20 ml, and particularly 15 ml. The application time is typically 10 to 120 seconds per application, preferably 30 to 90 seconds, and most preferably about 60 seconds. The composition can be applied shortly before and / or after social contact. In this way, the compositions of the present invention help provide users / patients with increased social freedom and convenience, and effectively contribute to minimizing further spread of the virus. Therefore, the present invention helps to ultimately limit the incidence of coronavirus infection.

[0085] The compositions of the present invention can be used for the treatment and prevention of viral infections. In a preferred embodiment, the composition is used to prevent viral infections.

[0086] In one embodiment, the virus belongs to the family Coronaviridae, and is preferably SARS-CoV-2. Alternatively, the virus is a common human coronavirus selected from 229E, NL63, OC43, and HKU1. In another embodiment, the virus belongs to the family Orthomyxoviridae, Paramyxoviridae, Filoviridae, or Picornaviridae. In a preferred embodiment, the virus is not an influenza A virus, and especially not an avian influenza virus. In a particularly preferred embodiment, the virus is an enveloped virus.

[0087] Example

[0088] Example 1:

[0089] A composition comprising these components is obtained by mixing the components described in Table 1 below.

[0090] Table 1: Components of Example 1

[0091] Element Quantity, in wt.-% water Add 100 Sorbitol 15 Xylitol 1.5 Hydroxyapatite 0.62 Phenoxyethanol 0.3 Sodium benzoate 0.15 Zinc PCA 0.3 PEG-40 hydrogenated castor oil 0.7 Cellulose gum 0.6 Sodium dodecyl sulfate 0.7 Sodium myristoyl sarcosinate 0.05 Sodium methylcocoyl taurate 0.09 Sodium saccharin 0.05 lactoferrin 0.03 Sodium hyaluronate 0.1 Phosphoric acid 0.1

[0092] Example 2:

[0093] The antiviral efficacy of the composition of Example 1 against bovine coronavirus (BcoV) under dirty conditions was measured by quantitative suspension test (80% v / v dilution) according to DIN EN 14476 (2013+A2:2019).

[0094] After treatment with the composition of Example 1 and a 30-second contact time, the viral load of bovine coronavirus decreased to undetectable levels (in the LVP (Large Volume Procedure) method, the 1g-TCID50 (median tissue culture infection dose) reduction factor was 5.50, and the titer reduction exceeded 4g). Therefore, the coronavirus was completely inactivated by the composition of Example 1, and when diluted at 80% (v / v), bovine coronavirus replication was undetectable in PT cell cultures at 20°C for 30 seconds. The results are summarized in Table 2 below.

[0095] Table 2: Antiviral activity against bovine coronavirus

[0096]

[0097] Example 3:

[0098] According to DIN EN 14476 (2013+A2:2019), the antiviral efficacy of the composition of Example 1 (80% or 50% v / v dilution) against SARS-CoV-2 (derived from patient isolates) under dirty conditions was measured. The procedure of DIN EN 14476 was modified by using artificial nasal secretions as an interfering substance (see also Meister et al., The Journal of Infectious Diseases 2020, 222, pp 1289-1292 for information on the use of artificial nasal secretions as an interfering substance). For the preparation of the artificial nasal secretions, 25 μl of BSA stock solution (0.5 g BSA in 10 ml phosphate buffer), 100 μl of mucin stock solution (0.04 g bovine mucin in 10 ml phosphate buffer) and 35 μl of yeast extract stock solution (0.5 g yeast extract in 10 ml phosphate buffer) were mixed.

[0099] Example 1 in the 80.0 v / v assay was active after 30 seconds of exposure. Since no residue was found in 576 cell culture units after 30 seconds, the result according to the Poisson formula was ≤1.84lg TCID50. Therefore, the reduction factor is ≥4.69 (6.53lg TCID50 minus ≤1.84lg TCID50). This corresponds to 99.99% inactivation. The results are summarized in Table 3 below.

[0100] Table 3: Antiviral activity against SARS-CoV-2

[0101]

[0102] Example 4:

[0103] The antiviral efficacy of the composition of Example 1 (80%, 40% and 20% v / v dilutions) against modified Ankara vaccinia virus under dirty conditions was measured according to DIN EN 14476:2019-10.

[0104] The composition of Example 1 was tested under dirty conditions in 20.0%, 40.0%, and 80.0% solutions, and the reduction in viral titer was measured after a 30-second exposure time. Due to the cytotoxicity of the test product, the inactivation test with an 80.0% solution of the test product could not demonstrate a reduction of 4 log10. Therefore, a high-volume electroplating (LVP) method was performed. In LVP, a high volume of the lowest non-cytotoxic dilution of the inactivation assay test mixture was added to the test cell line, and the virus-specific activity of the culture was monitored. According to the Poisson equation of the LVP method, under dirty conditions, the total viral load in the test mixture was 7.00g TCID50 / ml, resulting in a 4.12g reduction in TCID50 / ml. Therefore, an 80.0% solution of the composition of Example 1 exhibited excellent antiviral activity against modified Ankara vaccinia virus after 30 seconds of exposure under dirty conditions as an interfering substance.

[0105] In summary, the 80% v / v solution of Example 1 effectively inactivated the modified Ankara vaccinia virus under ambient, dirty conditions and an exposure time of 30 seconds. The results are summarized in Table 4 below.

[0106] Table 4: Antiviral activity against modified Ankara vaccinia virus

[0107]

[0108] According to the "Guidance on the Biocidal Products Regulation" Volume II, Parts B and C, the composition can be reasonably and effectively generalized to be generally active against enveloped viruses based on its specific efficiency against modified Ankara vaccinia virus.

[0109] Example 5:

[0110] Clinical trials were conducted using the composition of Example 1 to obtain in vivo data (see also Schürmann et al. European archives of oto-rhino-laryngology, 2021, “Mouthrinses against SARS-CoV-2: anti-inflammatory effectivity and a clinical pilot study”). A total of 29 adult hospitalized patients who tested positive for SARS-CoV-2 were recruited. Pharyngeal swabs were collected using a standardized protocol before and 5 minutes after gargling and sent to an experienced laboratory for clinical diagnosis to perform real-time polymerase chain reaction (rt-PCR), analyze the cycle threshold (CT) of the samples, and detect SARS-CoV-2. Based on a rough estimate of the slope of the calibration curve, increases in CT values ​​after 1, 2, 3, and 4 cycles corresponded to reductions in viral load of approximately 55%, 73%, 86%, and 93%, respectively. The overall mean CT value before rinsing was 26.0, and the median CT value was 28.0. The overall mean CT value after rinsing was 29.1, and the median CT value was 31.0. The mean showed an increase in CT value of 3.1, indicating a reduction in viral load in the pharynx of approximately 90%. Therefore, the composition of Example 1 shows effectiveness in treating and preventing coronavirus infection. The increase in CT value (reduction in viral load) was statistically significant (p < 0.00001, two-sided, exact Wilcoxon test). The results are summarized in Table 5 below.

[0111] Table 5: CT-value results after rinsing with mouthwash

[0112] To investigate the temporal development of viral load in the pharynx, viral load was sampled from five patients at different time points (0, 2, 4, and 6 hours) after gargling. Viral load recovered to its initial level in approximately six hours. Figure 1 As shown, highly infectious patients were able to recover their initial viral load during this period, while less infectious patients were unable to recover their initial infectivity 6 hours after gargling.

Claims

1. Use of a composition comprising 0.01 to 5 wt% hydroxyapatite in the preparation of an agent for the treatment and / or prevention of enveloped virus infection. The composition further comprises less than or equal to 1 wt% of a surfactant; wherein the surfactant comprises a mixture of surfactant A, surfactant B, and surfactant C; surfactant A is an alkyl sulfate, and its content in the composition ranges from 0.1 to 0.9 wt%; surfactant B is an alkyl taurine, and its content in the composition ranges from 0.01 to 0.2 wt%; surfactant C is an alkyl sarcosine, and its content in the composition ranges from 0.001 to 0.06 wt%. The composition further comprises 0.01 to 0.5 wt% of a water-soluble zinc salt selected from zinc L-pyrrolidone carboxylate, zinc acetate, zinc chloride, zinc histidine, zinc gluconate, zinc aspartate, zinc citrate, zinc sulfate, zinc lactate, and mixtures thereof; and The reagent is mouthwash or aerosol.

2. The use according to claim 1, wherein the composition further comprises 0.001 to 5 wt% of a polyol selected from erythritol, arabinitol, lactitol, maltitol, mannitol, sorbitol, xylitol, and mixtures thereof.

3. The use according to claim 1, wherein the surfactant A is sodium dodecyl sulfate, the surfactant B is sodium methylcocoyl taurate, and the surfactant C is sodium myristoyl sarcosinate.

4. The use according to claim 2, wherein the polyol is sorbitol and / or xylitol.

5. The use according to any one of claims 1 to 4, wherein the composition does not contain ethanol or contains 0.001 to 60 wt% ethanol.

6. The use according to any one of claims 1 to 4, wherein the composition further comprises 0.001 to 5 wt% of a component selected from eucalyptol, thymol, menthol, anise oil, fennel oil and levonerol.

7. The use according to any one of claims 1 to 4, wherein the composition comprises transferrin.

8. The use according to claim 7, wherein the composition comprises lactoferrin.

9. The use according to any one of claims 1 to 4, wherein the composition further comprises a film-forming polymer selected from carrageenan, carboxymethyl cellulose (CMC) and pharmaceutically acceptable salts thereof, hydroxypropyl methylcellulose (HPMC), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid and pharmaceutically acceptable salts thereof, copolymers of methyl vinyl ether and maleic acid and pharmaceutically acceptable salts thereof, carboxymethyl chitin, polyvinylpyrrolidone, chitosan, and mixtures thereof.

10. The use according to any one of claims 1 to 4, wherein the composition further comprises a water-insoluble zinc salt.

11. The use according to any one of claims 1 to 4, wherein the reagent is formulated for application to a mucosa.

12. The use according to claim 11, wherein the reagent is formulated for application to mucous membranes via a spray device.

13. The use according to any one of claims 1 to 4, wherein the virus belongs to the Coronaviridae family.

14. The use according to claim 13, wherein the virus is SARS-CoV-2.

15. A composition comprising 0.01 to 5 wt% hydroxyapatite, 0.01 to 0.5 wt% of a water-soluble zinc salt, wherein the water-soluble zinc salt is selected from zinc L-pyrrolidone carboxylate, zinc acetate, zinc chloride, zinc histidine, zinc gluconate, zinc aspartate, zinc citrate, zinc sulfate, zinc lactate, and mixtures thereof. A surfactant of 1 wt% or less; wherein the surfactant comprises a mixture of surfactant A, surfactant B, and surfactant C; wherein surfactant A is an alkyl sulfate and is present in the composition at a concentration of 0.1 to 0.9 wt%; wherein surfactant B is an alkyl taurate and is present in the composition at a concentration of 0.01 to 0.2 wt%; wherein surfactant C is an alkyl sarcosinate and is present in the composition at a concentration of 0.001 to 0.06 wt%. 0.001 to 5 wt% of a polyol, said polyol being selected from erythritol, arabinitol, lactitol, maltitol, mannitol, sorbitol, xylitol, and mixtures thereof. The composition is a mouthwash or aerosol.

16. The composition according to claim 15, wherein the surfactant A is sodium dodecyl sulfate, the surfactant B is sodium methylcocoyl taurate, and the surfactant C is sodium myristoyl sarcosinate.

17. The composition according to claim 15, wherein the polyol is sorbitol and / or xylitol.

18. The composition according to any one of claims 15 to 17, wherein the composition does not contain ethanol or contains 0.001 to 60 wt% ethanol.

19. The composition according to any one of claims 15 to 17, wherein the composition further comprises 0.001 to 5 wt% of a component selected from eucalyptol, thymol, menthol, anise oil, fennel oil and levonerol.

20. The composition according to any one of claims 15 to 17, wherein the composition comprises transferrin.

21. The composition of claim 20, wherein the composition comprises lactoferrin.

22. The composition according to any one of claims 15 to 17, wherein the composition further comprises a film-forming polymer selected from carrageenan, carboxymethyl cellulose (CMC) and pharmaceutically acceptable salts thereof, hydroxypropyl methylcellulose (HPMC), ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hyaluronic acid and pharmaceutically acceptable salts thereof, copolymers of methyl vinyl ether and maleic acid and pharmaceutically acceptable salts thereof, carboxymethyl chitin, polyvinylpyrrolidone, chitosan, and mixtures thereof.

23. The composition according to any one of claims 15 to 17, wherein the composition further comprises a water-insoluble zinc salt.

24. The composition according to any one of claims 15 to 17, wherein the composition is formulated for application to a mucosa.

25. The composition of claim 24, wherein the composition is formulated for application to a mucosa via a spray device.

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