Novel chlorhexidine salts and related compositions and methods

Abstract

The present application relates to novel chlorhexidine lauryl sulfate salts that provide enhanced chlorhexidine stability and enhanced antibacterial activity, as well as to formulations and methods of using the novel salts.

Description

Field of the Invention

[0001] This application relates to a novel complex of lauryl sulfate and chlorhexidine, which provides enhanced chlorhexidine stability and antibacterial activity. Background of the Invention

[0002] Chlorhexidine (CHX) is widely used in mouthwashes to treat gingivitis, help prevent dental plaque and caries, and prevent infections after oral surgery and tooth extraction. Generally, chlorhexidine is provided in the form of chlorhexidine gluconate (CHG). Chlorhexidine can also be used for skin disinfection before surgery, sterilization of surgical instruments, cleaning wounds, treating oral yeast infections, and preventing catheter blockage. However, chlorhexidine may degrade during storage, and the formulation may affect its antibacterial efficacy. There is a need to provide improved chlorhexidine formulations with enhanced stability and antibacterial efficacy. Summary of the Invention

[0003] Unexpectedly, it has been found that the novel chlorhexidine lauryl sulfate complex (CHX-LS, also sometimes referred to herein as chlorhexidine dodecyl sulfate or CHX-DS) provides enhanced chlorhexidine stability and antibacterial activity, for example in oral care compositions.

[0004] Based on the detailed description provided below, additional applicable fields of the present invention will become apparent. The detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention. Brief Description of the Drawings

[0005] Figure 1 The NMR results of CHX-LS crystals dissolved in DMSO are depicted.

[0006] Figure 2 The comparison of the FTIR absorption spectra of CHX-DS (also known as CHX-LS) crystals prepared in this work with the FTIR absorption spectra of reference materials of SDS (also known as SLS) and CHG (chlorhexidine gluconate) is shown in Figure 2 (for clarity, the spectra are offset).

[0007] Figure 3 Two alternative three-dimensional structures of the salt are depicted.

[0008] Figure 4 The measurement of methanethiol by gas chromatography to evaluate the VSC reduction efficacy is depicted. Detailed Description

[0009] The following description of the preferred embodiments is exemplary in nature and is in no way intended to limit the invention, its application, or uses.

[0010] As used throughout, ranges are used as shorthand for describing each and every value within the range. Any value within the range can be selected as the endpoint of the range. Additionally, all references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the definitions in this disclosure and the definitions of the cited references, the definitions in this disclosure shall control.

[0011] Unless otherwise indicated, all percentages and amounts expressed herein and elsewhere in the specification are to be understood as weight percentages relative to the total composition. The amounts given are based on the active weight of the materials.

[0012] As is customary in the art, the compositions described herein are sometimes described in terms of their ingredients, although the ingredients may dissociate, associate, or react in the formulation. For example, ions are typically provided to the formulation in the form of salts, which may dissolve and dissociate in aqueous solution. It is understood that the invention encompasses both the mixtures of the described ingredients and the products obtained therefrom.

[0013] It is understood that all ingredients in the compositions described herein are safe and palatable at the relevant concentrations for oral administration as a mouthwash.

[0014] As described in the examples, chlorhexidine lauryl sulfate (CHX-LS) was synthesized and characterized by single-crystal X-ray diffraction (SC-XRD), 1H nuclear magnetic resonance (NMR), 1H nuclear Overhauser effect spectroscopy (NOESY), and attenuated total reflectance Fourier-transform infrared spectroscopy (ATR-FTIR). The solid-state structure contains a 1:2 stoichiometric ratio of the chlorhexidine cation [C22H30Cl2N10]2+ to the dodecyl sulfate anion [C12H25SO4]-. Compared to chlorhexidine gluconate (CHG), CHX-LS exhibits broad-spectrum antibacterial activity and shows excellent efficacy in reducing volatile sulfur compounds (VSCs) produced by bacteria. Unexpectedly, although anionic surfactants such as sodium lauryl sulfate may interfere with the activity of CHX, providing CHX as a stable complex with lauryl sulfate seems to enhance its activity.

[0015] In one embodiment, the present disclosure provides a solid salt of chlorhexidine lauryl sulfate (Compound 1). For example, the present disclosure provides:

[0016] 1.1. Compound 1, in crystalline form.

[0017] 1.2. Compound 1, in amorphous form.

[0018] 1.3. Any of the foregoing compounds, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:2.

[0019] 1.4. Any of the foregoing compounds having a structure (a) in which two LS anions are each paired with the protonated guanidine moiety of the CHX molecule, or a structure (b) in which two LS molecules are both paired with a single di - protonated guanidine moiety of the CHX molecule.

[0020] 1.5. Any of the foregoing compounds having a structure corresponding to Structure A or Structure B:

[0021]

[0022] 1.6. Any of the foregoing compounds having a structure corresponding to Structure A.

[0023] In another embodiment, the present disclosure provides an oral care composition (Composition 1) comprising chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:2. For example, the present disclosure provides:

[0024] 1.1. Composition 1, wherein the chlorhexidine lauryl sulfate is a solid salt of chlorhexidine lauryl sulfate according to Compound 1 and the like.

[0025] 1.2. Composition 1 or 1.1, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is about 1:2.

[0026] 1.3. Composition 1, 1.1 or 1.2, wherein the chlorhexidine lauryl sulfate is in crystalline form.

[0027] 1.4. Composition 1, 1.1 or 1.2, wherein the chlorhexidine lauryl sulfate is in amorphous form.

[0028] 1.5. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate has a structure in which two LS molecules are each paired with a different guanidine Partially paired structure (a), or where both LS molecules are each single guanidines of a CHX molecule Partially paired structure (b).

[0029] 1.6. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate has a structure corresponding to Structure A, or wherein the chlorhexidine lauryl sulfate has a structure corresponding to Structure B.

[0030] 1.7. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate has a structure corresponding to Structure A.

[0031] 1.8. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate is added to other formulation excipients as a preformed solid salt, such as a solid salt according to any one of Compound 1 and the like.

[0032] 1.9. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate is added to the formulation excipients as preformed solid salt crystals.

[0033] 1.10. Any of the foregoing compositions, wherein the chlorhexidine lauryl sulfate is insoluble or partially insoluble.

[0034] 1.11. Any of the foregoing compositions, in the form of a mouthwash; a non-abrasive gel; or a toothpaste or gel containing an abrasive.

[0035] 1.12. Any of the foregoing compositions, further comprising a flavoring agent, a sweetening agent, a humectant, and a surfactant.

[0036] 1.13. Any of the foregoing compositions, in the form of a mouthwash, the composition further comprising a flavoring agent, a sweetening agent, a humectant, and a surfactant.

[0037] 1.14. Any one of Compositions 1 to 1.11, in the form of a toothpaste, the composition further comprising a flavoring agent, a sweetening agent, a humectant, a surfactant, and an abrasive.

[0038] 1.15. Any of the foregoing compositions, comprising one or more nonionic surfactants.

[0039] 1.16. The foregoing composition, wherein the nonionic surfactant comprises a fatty acid moiety and a polyethylene glycol moiety.

[0040] 1.17. The foregoing composition, wherein the nonionic surfactant is selected from PEG-40 sorbitan diisostearate and PEG-40 hydrogenated castor oil.

[0041] 1.18. Any of the foregoing compositions, comprising a sweetening agent, such as a non-saccharide sweetening agent, such as sodium saccharin.

[0042] 1.19. Any of the foregoing compositions comprises a humectant, such as a humectant selected from propylene glycol, glycerol, sorbitol, and combinations thereof.

[0043] 1.20. Any of the foregoing compositions comprises glycerol.

[0044] 1.21. Any of the foregoing compositions comprises cetylpyridinium chloride , for example, the amount of the cetylpyridinium chloride is 0.01% to 0.05% by weight, for example about 0.015%.

[0045] 1.22. Any of the foregoing compositions comprises a fluoride ion source, such as a fluoride ion source selected from sodium fluoride, stannous fluoride, sodium monofluorophosphate, amine fluorides (such as orlafluor and / or delmopinol), and combinations thereof, for example, the amount of the fluoride ion source provides 200 ppm to 500 ppm of fluoride in a mouthwash, for example about 225 ppm of fluoride, or provides 1000 ppm to 5000 ppm of fluoride in a toothpaste, for example about 1450 ppm of fluoride.

[0046] 1.23. Any of the foregoing compositions, wherein the concentration of chlorhexidine lauryl sulfate is 0.05% to 0.4% by weight.

[0047] 1.24. Any of the foregoing compositions, wherein the concentration of chlorhexidine lauryl sulfate is 0.05% to 0.25% by weight.

[0048] 1.25. Any of the foregoing compositions, wherein the concentration of chlorhexidine lauryl sulfate is about 0.25% by weight.

[0049] 1.26. Any one of Compositions 1 to 1.23, wherein the concentration of chlorhexidine lauryl sulfate is 0.1% to 0.2% by weight.

[0050] 1.27. Any of the foregoing compositions comprises at least 70% by weight of water.

[0051] 1.28. Any of the foregoing compositions comprises 5% to 25% by weight of a humectant.

[0052] 1.29. Any of the foregoing compositions is in the form of a mouthwash.

[0053] 1.30. Any of the foregoing compositions comprises:

[0054] 0.1% to 0.15% of chlorhexidine lauryl sulfate;

[0055] 0% to 15% of ethanol;

[0056] 5% to 25% of a humectant selected from propylene glycol, glycerin, sorbitol, and combinations thereof;

[0057] 0% to 0.02% of cetylpyridinium chloride

[0058] 0.1% to 1% of a nonionic surfactant, such as a nonionic surfactant selected from PEG-40 sorbitan diisostearate, PEG-40 hydrogenated castor oil, and combinations thereof; a flavoring agent; a coloring agent; and water;

[0059] wherein all percentage amounts are by weight of the composition.

[0060] 1.31. Any of the foregoing compositions that does not contain ethanol.

[0061] 1.32. Any of the foregoing compositions that does not contain chlorhexidine gluconate.

[0062] 1.33. Any of the foregoing compositions that does not contain orally unacceptable ingredients, such as substances that are not safe and / or palatable at relevant concentrations for use in oral care formulations such as mouthwashes or toothpastes.

[0063] 1.34. Any of the foregoing compositions that exhibits improved chlorhexidine stability after aging in an oven at 60 °C for at least 3 weeks, such as at least 6 weeks, relative to an aqueous formulation containing the same amount of chlorhexidine in the form of chlorhexidine gluconate rather than chlorhexidine lauryl sulfate.

[0064] 1.35. Any of the foregoing compositions for treating gingivitis, reducing dental plaque and dental caries, treating oral yeast infections, and / or preventing infections after oral surgery and tooth extraction.

[0065] 1.36. Any of the foregoing compositions for reducing bad breath, such as for reducing volatile sulfur compounds in the oral cavity.

[0066] 1.37. Any of the foregoing compositions used as an antimicrobial agent.

[0067] In another embodiment, the present disclosure provides:

[0068] A method for treating gingivitis,

[0069] A method for preventing dental plaque and dental caries,

[0070] A method for treating oral yeast infections,

[0071] A method for preventing infections after oral surgery and tooth extraction,

[0072] A method for reducing bad breath, such as for reducing volatile sulfur compounds in the oral cavity, and / or

[0073] Method for treating or reducing harmful bacteria in the oral cavity

[0074] The method includes administering to the oral cavity of a subject in need thereof an oral care composition comprising chlorhexidine (CHX) and lauryl sulfate (LS) in a molar ratio of 1:4 to 1:1, such as about 1:2, for example, administering an oral care composition according to any one of Composition 1 and the like, for example, once, twice or three times a day.

[0075] For example, in one embodiment of any of the foregoing methods for treating gingivitis, preventing dental plaque and dental caries, treating yeast infections of the oral cavity, preventing infections after oral surgery and tooth extraction, and / or reducing bad breath, the oral care composition, for example, an oral care composition according to any one of Composition 1 and the like, is a mouthwash, and the mouthwash can be administered to a subject in need thereof twice a day by rinsing for about 30 seconds with a dose of about 15 ml of undiluted mouthwash after brushing teeth in the morning and evening. The patient should be instructed not to rinse with water or other mouthwashes, not to brush teeth, or not to eat immediately after using the mouthwash. The mouthwash is not intended to be ingested and should be spat out after rinsing.

[0076] In another embodiment, the present disclosure provides a disinfectant composition (Composition 2) comprising chlorhexidine lauryl sulfate, water, and an alcohol (e.g., ethanol, isopropanol, and mixtures thereof), for example, a composition comprising 1% to 5% chlorhexidine lauryl sulfate, 65% to 80% isopropanol, and water, wherein the molar ratio of chlorhexidine (CHX) to lauryl sulfate (LS) is 1:4 to 1:1, such as about 1:2; for example, wherein chlorhexidine lauryl sulfate is according to any one of Compound 1 and the like, for example, wherein Composition 2 is formed by mixing any one of Compound 1 and the like with water and other excipients, for example, used as a skin disinfectant before surgery, sterilization of surgical or dental instruments, cleaning wounds, and / or for preventing catheter blockage.

[0077] In another embodiment, the present disclosure provides a method for skin disinfection before surgery, the method including administering to the skin of a patient in need thereof a liquid composition comprising water and chlorhexidine lauryl sulfate in a molar ratio of chlorhexidine (CHX) to lauryl sulfate (LS) of 1:4 to 1:1, such as about 1:2, for example, a liquid composition according to any one of Composition 2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients.

[0078] In another embodiment, the present disclosure provides a method for treating or inhibiting a topical infection of the skin, the method comprising administering to the skin of a patient in need thereof a composition (e.g., a liquid or a cream) comprising water and chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients, such as a composition according to any one of Composition 2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients.

[0079] In another embodiment, the present disclosure provides a method for sterilizing surgical or dental instruments, the method comprising administering to the instruments a liquid composition comprising water and chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:2, for example, a liquid composition according to Composition 2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients.

[0080] In another embodiment, the present disclosure provides a method for cleaning a wound, the method comprising administering to the wound a liquid composition comprising water and chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:2, for example, a liquid composition according to any one of Composition 2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients.

[0081] In another embodiment, the present disclosure provides a method for preventing catheter blockage, the method comprising flushing the catheter with a liquid composition comprising water and chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:2, for example, a liquid composition according to any one of Composition 2, for example, wherein the composition is formed by mixing any one of Compound 1 and the like with water and other excipients.

[0082] In another embodiment, the present disclosure provides a method for stabilizing chlorhexidine in an aqueous preparation, such as a composition according to any one of Composition 1 and the like or Composition 2, the method comprising adding chlorhexidine in the form of a solid salt of chlorhexidine lauryl sulfate, such as in the form of any one of Compound 1 and the like, to the solution.

[0083] As used herein, "oral care composition" such as the mouthwashes and toothpastes of the present disclosure refers to a composition whose intended use includes oral care, oral hygiene, and / or oral appearance or whose intended method of use includes administration to the oral cavity, and refers to a composition that is palatable and safe for topical administration to the oral cavity and providing benefits to teeth and / or the oral cavity. Thus, the term "oral care composition" expressly excludes compositions that are highly toxic, unpalatable, or otherwise unsuitable for administration to the oral cavity. In some embodiments, the oral care composition is not intended to be swallowed, but rather remains in the oral cavity for a time sufficient to affect the intended utility. The oral care compositions disclosed herein can be used for non-human mammals such as companion animals (e.g., dogs and cats), as well as for human use. In some embodiments, the oral care compositions disclosed herein are for human use. In some embodiments, the present disclosure provides mouthwash formulations. In some embodiments, the present disclosure provides toothpaste formulations.

[0084] As used herein, "nonionic surfactant" generally refers to a compound produced by condensing an alkylene oxide group (inherently hydrophilic) with an organic hydrophobic compound that can be aliphatic or alkyl-aromatic in nature. Examples of suitable nonionic surfactants include poloxamers (sold under the trade name ), polyoxyethylene, polyoxyethylene sorbitan esters (sold under the trade name ), polyoxyethylene 40 hydrogenated castor oil, fatty alcohol ethoxylates, poly(ethylene oxide) condensates of alkylphenols, condensation products derived from the reaction product of ethylene oxide with propylene oxide and ethylenediamine, ethylene oxide condensates of aliphatic alcohols, alkyl polyglycosides (e.g., fatty alcohol ethers of polysaccharides, e.g., fatty alcohol ethers of polyglucosides, e.g., decyl ethers, lauryl ethers, octyl ethers, octanoyl ethers, myristyl ethers, stearyl ethers, and other ethers of glucose and polyglucoside polymers, including mixed ethers such as octyl / octanoyl (C8-10) glucoside, cocoalkyl (C8-16) glucoside, and lauryl (C12-16) glucoside, long-chain tertiary amine oxides, long-chain tertiary phosphine oxides, long-chain dialkyl sulfoxides, and mixtures of such substances.

[0085] In some embodiments, the nonionic surfactant includes amine oxides, fatty acid amides, ethoxylated fatty alcohols, block copolymers of polyethylene glycol and polypropylene glycol, glycerol alkyl esters, polyoxyethylene octylphenol ethers, sorbitan alkyl esters, polyoxyethylene sorbitan alkyl esters, and mixtures thereof. Examples of amine oxides include, but are not limited to, lauramidopropyl dimethylamine oxide, myristamidopropyl dimethylamine oxide, and mixtures thereof. Examples of fatty acid amides include, but are not limited to, coconut monoethanolamide, lauramide monoethanolamide, coconut diethanolamide, and mixtures thereof. In certain embodiments, the nonionic surfactant is a combination of an amine oxide and a fatty acid amide. In certain embodiments, the amine oxide is a mixture of lauramidopropyl dimethylamine oxide and myristamidopropyl dimethylamine oxide. In certain embodiments, the nonionic surfactant is a combination of lauryl / myristamidopropyl dimethylamine oxide and coconut monoethanolamide. In certain embodiments, the nonionic surfactant is present in an amount of from 0.01% to 5.0%, from 0.1% to 2.0%, from 0.1% to 0.6%, from 0.2% to 0.4%, about 0.2%, or about 0.5%.

[0086] Mouthwashes typically contain significant levels of ethanol, which is often required to dissolve essential oils and prevent bacterial contamination. High levels of ethanol may be undesirable because, in addition to the potential for ingestion abuse, ethanol can also exacerbate conditions such as dry mouth. Thus, in some embodiments, the oral care compositions of the present invention are substantially free of ethanol, e.g., contain less than 1% ethanol.

[0087] Humectants can increase the viscosity, mouthfeel, and sweetness of the product, and can also help preserve the product from deterioration or microbial contamination. Suitable humectants include edible polyols such as glycerol, sorbitol, xylitol, propylene glycol, and other polyols and mixtures of these humectants. Sorbitol can be provided in some cases as a hydrogenated starch hydrolysate in the form of a syrup, which mainly contains sorbitol (the product when starch is completely hydrolyzed to glucose and then hydrogenated), but may also contain other sugar alcohols such as mannitol, maltitol, and long-chain hydrogenated saccharides due to incomplete hydrolysis and / or the presence of saccharides other than glucose, and in such cases these other sugar alcohols also serve as humectants. In some embodiments, the humectant is present at a level of from 5% to 25% by weight, such as from 15% to 20%.

[0088] Flavoring agents useful in the present invention can include: extracts or oils from flavoring plants such as mint, spearmint, cinnamon, wintergreen, and combinations thereof; cooling agents such as menthol, methyl salicylate, and commercially available products such as OptaCool from Symrise; and sweetening agents, which can include polyols (which also serve as humectants), saccharin, acesulfame potassium, aspartame, neotame, stevia, and sucralose.

[0089] Toothpastes (including abrasive gels) according to the present disclosure may include one or more abrasives, such as silica abrasives or calcium abrasives, such as calcium carbonate, dicalcium phosphate, or calcium pyrophosphate. For example, the toothpaste compositions disclosed herein may include silica abrasives and may include additional abrasives, such as calcium phosphate abrasives, such as tricalcium phosphate (Ca3(PO4)2), hydroxyapatite (Ca 10 (PO4)6(OH)2) or dicalcium phosphate dihydrate (CaHPO4·2H2O, sometimes also referred to as DiCal) or calcium pyrophosphate; calcium carbonate abrasives; or abrasives such as sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite, or other siliceous materials; or combinations thereof. The average particle size of these abrasives generally ranges from about 1 micron to about 30 microns, about 5 microns to about 15 microns. These particulate silica abrasives are different from colloidal silica thickeners.

[0090] Toothpastes according to the present disclosure may also include anti-calculus (tartar control) agents. Suitable anti-calculus agents include, but are not limited to, phosphates and polyphosphates (such as pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphates, zinc citrate trihydrate, polypeptides, polyolefin sulfonates, polyolefin phosphates, diphosphonates. Thus, the present invention may include phosphates. In certain embodiments, these salts are alkali metal phosphates, i.e., salts of alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium salts, potassium salts, or calcium salts. As used herein, "phosphates" encompasses orally acceptable monophosphates and polyphosphates, such as P 1-6 phosphates, such as monomeric phosphates, such as dihydrogen phosphates, hydrogen diphosphates, or tribasic phosphates; dimeric phosphates such as pyrophosphates; and polyphosphates, such as sodium hexametaphosphate. In certain instances, the selected phosphates are selected from alkali metal hydrogen diphosphates and alkali metal pyrophosphates, such as selected from disodium hydrogen phosphate, dipotassium hydrogen phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more thereof. In one particular embodiment, for example, the composition includes a mixture of tetrasodium pyrophosphate (Na4P2O7), calcium pyrophosphate (Ca2P2O7), and disodium hydrogen phosphate (Na2HPO4), for example, in an amount of about 3% to 4% of disodium hydrogen phosphate and about 0.2% to 1% of each pyrophosphate. In another embodiment, the composition includes a mixture of tetrasodium pyrophosphate (TSPP) and sodium tripolyphosphate (STPP)(Na5P3O 10 )), for example, the proportion of TSPP is about 1% to 2%, and the proportion of STPP is about 7% to about 10%. Such phosphates are provided in an amount effective to reduce enamel erosion, contribute to cleaning teeth and / or reducing the amount of tartar accumulation on teeth, for example, in an amount of 2% to 20% by weight of the composition, for example, about 5% to 15%.

[0091] The oral care compositions disclosed herein may also include additional polymers to adjust the viscosity of the formulation or enhance the solubility of other ingredients and / or form gels. Such additional polymers include polysaccharides (such as cellulose derivatives, such as carboxymethyl cellulose, or polysaccharide gums, such as xanthan gum or carrageenan), and polyvinylpyrrolidone. Acidic polymers such as polyacrylate gels may be provided in the form of their free acids or partially or fully neutralized water-soluble alkali metal (such as potassium and sodium) salts or ammonium salts. Silica thickeners that form polymeric structures or gels in an aqueous medium may be present. Note that these silica thickeners are physically and functionally different from the particulate silica abrasives that are also present in some compositions, as the silica thickeners are very finely divided and provide little to no abrasive action. Additional thickeners are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose, and water-soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural gums such as karaya gum, gum arabic, and tragacanth gum may also be incorporated. Colloidal magnesium aluminum silicate may also be used as a component to thicken the composition to further improve the texture of the composition. In certain embodiments, thickeners are used in an amount of from 0.5% to 5.0% by weight of the total composition.

[0092] Other ingredients that may optionally be included in the compositions according to the invention include hyaluronic acid, green tea, ginger, sea salt, coconut oil, turmeric, white turmeric (curcumin), grape seed oil, ginseng, monk fruit, vitamin E, basil, chamomile, pomegranate, aloe vera, and charcoal. Any such ingredient may be present in an amount of from 0.01% to 2%, such as from 0.01% to 1%, or from 0.01% to 0.5%, or from 0.01% to 0.1% by weight of the composition.

[0093] As used herein, "orally acceptable" means a substance that is safe and palatable at the relevant concentrations for use in oral care formulations such as mouthwashes.

[0094] Unless otherwise indicated, all percentages of composition components given in this specification are by weight based on 100% of the total composition or formulation weight.

[0095] It should be understood that in some cases, one ingredient may perform multiple functions. For example, polyethylene glycol may affect the viscosity of the product but may also act as a humectant.

[0096] As is customary in the art, the compositions and formulations provided herein are described and claimed in terms of their ingredients. As will be apparent to those skilled in the art, in some cases the ingredients may react with each other such that the true composition of the final formulation may not exactly correspond to the listed ingredients. Accordingly, it should be understood that the invention extends to the products of the combinations of the listed ingredients.

[0097] As used throughout, ranges are used as a shorthand for describing each and every value within the range. Any value within the range can be selected as the endpoint of the range. Additionally, all references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the definitions in this disclosure and the definitions of the cited references, the present disclosure shall control.

[0098] Examples

[0099] Characterization of CHX-LS salt in Example 1

[0100] CHG and CHG-SLS mixture aging study: 2 grams of 20% CHG solution was used as a control, and SLS was added to another 2 grams of 20% CHG solution at a 1:2 molar ratio of SLS:CHG. The two aqueous solutions were placed in an oven at 60 °C and aged for 3 weeks and 6 weeks.

[0101] Sample preparation for CHX degradation analysis by GCMS analysis: The two aged solutions were removed from the 60 °C oven. They were diluted with methanol at a ratio of 1:3.5. The two solutions were filtered separately through a 0.20 μm PTFE filter, then they were diluted again with methanol at a dilution ratio of 1:10, and then transferred to ROBO autosampler vials for GC-MS analysis. A gas chromatography system 6890N (Agilent Technologies, Santa Clara, California, USA) with a 5972MS detector plus a Gerstel MPS-2 autosampler was used to detect CHX degradation products. Separation was accomplished using an HP-5MS GC column (30 m × 0.25 mm × 0.25 μm, length × inner diameter × film thickness, Agilent Technologies). 1 μL of the sample was injected in splitless mode. The oven temperature was initially held at 80 °C for 1 minute. Thereafter, the temperature was increased at 6 °C / minute until 300 °C and held for 2.33 minutes. The total run time was 40 minutes. Helium was used as the carrier gas and was delivered at a constant flow rate of 1 mL / minute (pressure 9.38 psi, velocity 37 cm / second). The injector temperature was set at 250 °C, and the interface temperature between the GC oven and the MS detector was 250 °C. The MS detector was adjusted with a standard spectrum, and MS data (total ion chromatogram, TIC) was acquired in full scan mode (m / z from 45 to 550) at a scan rate of 3 scans / second in electron ionization (EI) mode at an electron energy of 70 eV. The MS source temperature was 230 °C and the quat temperature was 150 °C.

[0102]

[0103] The relative degradation content in CHG-SLS aged at 60 °C for 3 weeks was only 4% of that seen in the CHG solution control. Even when aged at 60 °C for 6 weeks, the degradation content in the CHG-SLS mixture solution was only about 21% relative to the CHG blank control solution. These results clearly show that SLS can prevent CHX degradation. At the same time, new CHX-LS complex crystals were obtained from the CHG-SLS mixture.

[0104] NMR experiment: The crystal sample was completely dissolved in deuterated DMSO and prepared at 0.1 wt%. The ¹H NMR spectra were acquired using a Bruker spectrometer operating at a proton frequency of 500.13 MHz equipped with a dual resonance cryoprobe. 1 The sample temperature was controlled at 25 °C. The spectra were collected using a single pulse with a 30° pulse angle, 1 s acquisition time, 5 s recycle delay, and 12 ppm sweep width. The number of scans was 32, and each spectrum acquisition took approximately 10 minutes. 1 ¹H NMR spectral signals ( Figure 1 ) could be attributed to the structures of CHX and LS. Based on peak integration, the stoichiometric ratio between CHX and LS was 1:2.

[0105] X-ray experiment: Chlorhexidine lauryl sulfate (CHX-LS) containing chlorhexidine and sodium lauryl sulfate (sometimes called sodium dodecyl sulfate) was synthesized and characterized via single crystal X-ray diffraction measurements, showing a stoichiometry of [C 22 H 32 N 10 C l2 .[(C 12 H 25 O4S)2], in which the molecules are arranged in a 1:2 ratio, with one doubly protonated chlorhexidine cation and two dodecyl sulfate anions.

[0106] Crystals of CHX-LS suitable for X-ray crystallography were isolated under a microscope and used with a Cu Kα INCOATEC ImuS microfocus source X-ray diffraction data were collected on a Bruker D8 Venture PHOTON 100 CMOS system. Data were collected at 100 K. Indexing was carried out using APEX3 (differential vector method). Data integration and reduction were performed using SaintPlus 6.01. Absorption correction was carried out by the multi-scan method implemented in SADABS. The space group was determined using XPREP implemented in APEX3. The structure was solved using SHELXT (direct method) and refined using SHELXL-2017 (F2-based full-matrix least-squares) via the OLEX2 interface program. All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were located in geometrically calculated positions and included in the refinement process using the riding model. Figure 3 The putative 3D structure of the crystal is depicted in Figure 3 , where one CHX pairs with two LS molecules. This is thought to be related to the inhibition of CHX metabolism. The 1:2 stoichiometry between CHX and LS is consistent with 1 the H NMR spectral signals ( Figure 1 ).

[0107] To further confirm the formation of the CHX-DS complex, the crystal was dissolved in methanol and analyzed by NMR and MS. Additionally, SC-XRD analysis was carried out at 100 K, showing that the coordination complex CHX-DS crystallizes in the triclinic P1 space group, with unit cell parameters and α = 70.24(10)°; β = 92.95(10)°; γ = 89.76(2)°. The structural formula can be described as [C 22 H 32 N 10 Cl2]·[(C 12 H 25 O4S)2] with an asymmetric unit consisting of one molecule of the di-protonated chlorhexidine cation and two molecules of the dodecyl sulfate anion. The structure contains one CHX molecule surrounded by two DS molecules, whereby the biguanide moiety of CHX is symmetrically protonated by hydrogen transfer from the acidic sulfate groups of two DS molecules. As can be seen from the C-N bond lengths ( to )It is evident that in these biguanide moieties, delocalization of single and double bonds is shown. The CHX dication adopts a helical conformation, resulting in a U-shaped coil extending parallel to the a-axis. The CHX cations in the coils between adjacent layers along the c-axis are oriented in opposite directions to each other, resulting in alternating layers of CHX coils, which are further involved in hydrogen-bonding interactions with the sulfate anions of the DS molecules (one of the DS molecules is disordered). Each of the CHX cations is involved in hydrogen-bonding interactions with sulfate groups from three different DS molecules. Two sulfate groups form two hydrogen bonds with the biguanide groups on the periphery, and one sulfate forms three hydrogen bonds with the internal -NH and -NH2 groups of the biguanide moiety. The H-bonds are in the to range, indicating strong hydrogen bonding. The PXRD pattern calculated from the single crystal structure also matches quite well with the PXRD pattern obtained from the bulk sample, indicating bulk phase purity.

[0108] FTIR experimental results: The CHX-LS crystals were analyzed in the FTIR spectrum. Peaks around 1400 cm -1 to 1800 cm -1 are very similar to the red SLS standard. Peaks from 800 cm -1 to 1300 cm -1 and from 2000 cm -1 to 3000 cm -1 match the CHX standard. Thus, the crystals contain both CHX and LS components.

[0109] Infrared spectra were collected using a Bruker Vertex 70 FTIR spectrometer (Bruker Optics, Billerica, Massachusetts) equipped with a GladiATR diamond ATR accessory (Pike technologies, Madison, Wisconsin). Spectra were acquired at a resolution of 4 cm-1 in the spectral range from 80 cm-1 to 4000 cm-1. All measurements were carried out at room temperature.

[0110] Figure 2 Shown is a comparison of the FTIR absorption spectra of the CHX-DS (or CHX-LS) crystals prepared in this work with the FTIR absorption spectra of reference materials of SDS (sodium dodecyl sulfate, sometimes also called sodium lauryl sulfate or SLS) and CHG (chlorhexidine gluconate) (for clarity, the spectra are offset). Analysis of the CHX-DS infrared spectrum immediately shows the presence of both the CHX component and the SDS component in the sample. As an example, in the region above 1500 cm -1 the CHX bands corresponding to ν(C=C), ν(C=N) and δ(NH2) vibrations are clearly seen, and at 3000 cm-1 -NH, =NH, and NH2 functional group N-H stretching modes in the range of 1 to 3500 cm -1 Similarly, the SDS component can be identified by a prominent band group associated with the νas(SO2) vibration in the region of 1200 cm-1 to 1275 cm-1 and strong νas / sym(CH3 / CH2) vibrations in the range of 2800 cm -1 to 3000 cm -1 The signs of both CHX and SDS vibration characteristics in the FTIR spectrum of the prepared crystal, combined with the fact that the absorption bands are significantly different from the reference material in terms of their shape and position, indicate the formation of a salt between chlorhexidine and sodium dodecyl sulfate ions.

[0111] LC-MS analysis results: The obtained crystal was dissolved in a methanol solvent and injected into a Thermo Q Exactive hybrid quadrupole-orbitrap mass spectrometer. The analyte CHX-LS solution was delivered with a mobile phase containing 50% MeOH-water solvent. The MS detector was operated in positive mode. The peak at 505 m / z represents pure chlorhexidine with a chlorine isotope pattern. It also gave complexes formed between chlorhexidine and LS at 771 and 1059, corresponding to CHX-LS with 1:1 and 1:2 molar ratios, respectively. The MS of pure chlorhexidine and the chlorhexidine complex with a 1:1 ratio may come from the fragmentation of the chlorhexidine with a 1:2 ratio.

[0112] One proposed CHX-LS structure is Structure A.

[0113]

[0114] Alternatively, as Figure 3 and depicted in the following Structure B, the sulfate moiety can pair with the same guanidine group:

[0115]

[0116] Example 2: Formation of CHX-LS salt from different concentrations of CHX and LX

[0117] A series of experiments were conducted to test the CHG:SLS molar ratio required to form the CHX-LS complex. It was found that the CHX-LS complex prepared from CHG and SLS formed only at specific ratios of CHG:SLS, typically a molar ratio of at least 1:4 (≥0.25), such as 1:1 or 1:2, at a concentration of 0.12 wt% CHG. In cases where the amount of CHG relative to SLS was low, such as when the molar ratio of CHX:LS was 1:5 or less (≤0.2), no detectable salt or precipitate was formed.

[0118] Existing oral care products typically use very low CHG:SLS ratios. For example, CHG is typically used at 0.12% by weight, while SLS is used at >1% by weight. The molar ratio of CHG to SLS in a solution of 0.12% CHG and 1% SLS by weight would be only about 0.03, well below the 0.25 or greater CHX / SLS molar ratio required to start forming precipitates with an aqueous solution of 0.12% CHG. Thus, it is expected that no solid salt precipitates will be present in such products.

[0119] Example 3: Antibacterial efficacy and VSC reduction using CHX-LS salt

[0120] Methanethiol was used as a model sulfur compound to study the in vitro efficacy of chlorhexidine lauryl sulfate (CHX-LS) in reducing volatile sulfur compounds (VSCs). It was determined that CHX-LS exhibited excellent antibacterial efficacy and a greater reduction in volatile sulfur compounds (VSCs) compared to chlorhexidine gluconate (CHG).

[0121] Clear solutions were prepared and used as precursors without purification. 10 wt% and 20 wt% solutions were prepared in anhydrous methanol using sodium lauryl sulfate (SLS) and chlorhexidine gluconate (CHG), respectively. Both samples were sonicated to ensure complete dissolution. The sodium lauryl sulfate solution was added dropwise to the CHG solution. A substance with a crystalline "snowflake" appearance formed after a few minutes.

[0122] Methanethiol (CH3SH, CAS#74-93-1) is a representative component of volatile sulfur compounds (VSCs) and can be used as a marker for quantitatively measuring oral odor by gas chromatography-flame photometric detector technology. Sample preparation requires dissolving CHX-LS, SLS, CHX-HCl, and the powder to a final concentration of 0.01 wt%; in addition, a 0.01 wt% CHG solution was also prepared. Hydroxyapatite (HAP) was incubated with whole saliva to form a pellicle, followed by treatment with test and control dentifrice slurries. After rinsing, the treated discs were transferred to headspace vials and incubated with the VSC solution to simulate oral odor (VSC) generation. Methanethiol in the headspace was measured by gas chromatography-flame photometric detector, and the product efficacy in reducing oral odor was determined.

[0123] Figure 4 The effects of CHX-LS, CHG, CHX-HCl, SLS, and methanol on volatile sulfur compounds (VSCs) produced by bacteria in vitro were shown by methanethiol gas chromatography (GC) headspace measurements. Statistical grouping calculated using the Tukey method and 95.0% confidence intervals indicated that for malodorous VSCs, CHX-LS and CHX-HCl were superior to the other test materials. InFigure 4 In it, the letters represent statistical groups. The means that do not share letters are significantly different. The lower the data, the better the VSC reduction efficacy. CHX-LS has significantly better methanethiol reduction efficacy than CHG and SDS. There is no significant difference among CHG, SLS, and methanol.

[0124] This study shows that CHX-LS exhibits excellent VSC reduction efficacy compared to CHG. These data indicate that CHX-LS is a viable and effective antimicrobial agent for malodor reduction in dentifrices and mouthwashes.

[0125] Although the present disclosure has been described with respect to specific examples, including the presently preferred modes of carrying out the present disclosure, those skilled in the art will understand that there are many variations and permutations of the above systems and techniques. It should be understood that other embodiments may be utilized and structural and functional modifications may be made without departing from the scope of the present disclosure.

Claims

1. A solid salt of chlorhexidine lauryl sulfate.

2. The salt according to claim 1, in crystalline form.

3. The salt according to claim 1, in amorphous form.

4. The salt of chlorhexidine lauryl sulfate according to any one of the preceding claims, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as 1:

2.

5. An oral care composition comprising chlorhexidine lauryl sulfate, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as about 1:

2.

6. The composition according to claim 5, wherein the chlorhexidine lauryl sulfate is added as a pre-formed solid salt, such as the salt according to any one of claims 1 to 5, to other formulation excipients.

7. The composition according to claim 5 or 6, wherein the chlorhexidine lauryl sulfate is added as a pre-formed solid salt crystal to water and other formulation excipients.

8. The composition according to any one of claims 5 to 7, wherein the chlorhexidine lauryl sulfate is formed in situ by combining a solution of sodium lauryl sulfate with chlorhexidine, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is from 1:4 to 1:1, such as 1:

2.

9. The composition according to any one of claims 5 to 8, in the form of a mouthwash, the composition further comprising a flavoring agent, a sweetening agent, a humectant and a surfactant.

10. The composition according to any one of claims 5 to 8, in the form of a toothpaste, the composition further comprising a flavoring agent, a sweetening agent, a humectant, a surfactant and an abrasive.

11. The composition according to any one of claims 5 to 10, wherein the concentration of chlorhexidine lauryl sulfate is from 0.05% to 0.4% by weight, such as about 0.25% by weight.

12. A method for stabilizing chlorhexidine in an aqueous solution, comprising adding the chlorhexidine in the form of a solid salt of chlorhexidine lauryl sulfate, such as the salt according to any one of claims 1 to 4, to the solution.

13. A method for treating gingivitis, preventing dental plaque and dental caries, treating oral yeast infections and / or preventing infections after oral surgery and tooth extraction, comprising administering to the oral cavity of a patient in need thereof an oral care composition according to any one of claims 4 to 11, such as once, twice or three times a day.

14. A method for reducing bad breath, such as for reducing volatile sulfur compounds in the oral cavity, comprising administering to the oral cavity of a patient in need thereof an oral care composition according to any one of claims 4 to 11, such as once, twice or three times a day.

15. A disinfectant composition comprising chlorhexidine lauryl sulfate, water and alcohol.

16. A method for disinfecting the skin before surgery or cleaning a wound, comprising administering to the skin or the wound of a patient in need thereof the liquid composition according to claim 15.

17. A method for sterilizing surgical or dental instruments, comprising administering to the instruments the liquid composition according to claim 15.

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