Patent Application
20240199538
This application relates to a novel complex of lauryl sulfate and chlorhexidine, which provides enhanced chlorhexidine stability and anti-bacterial activity.
Chlorhexidine (CHX) is widely used in mouthwashes to treat gingivitis, to help prevent dental plaque and caries, and to protect against infections following oral surgery and tooth extraction. Usually, 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 yeast infections of the mouth, and keeping urinary catheters from blocking. Chlorhexidine, however, can degrade during storage, and the formulation can affect its antibacterial efficacy. Improved formulations of chlorhexidine, providing enhanced stability and antibacterial efficacy, are needed.
It is surprisingly found that a novel complex of chlorhexidine lauryl sulfate (CHX-LS, also sometimes referred to herein as chlorhexidine dodecyl sulfate or CHX-DS) provides enhanced chlorhexidine stability and anti-bacterial activity, for example in an oral care composition.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. The detailed description and specific examples, while indicating the preferred embodiment of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
Unless otherwise specified, all percentages and amounts expressed herein and elsewhere in the specification should be understood to refer to percentages by weight relative to the total composition. The amounts given are based on the active weight of the material.
As is usual in the art, the compositions described herein are sometimes described in terms of their ingredients, notwithstanding that the ingredients may disassociate, associate, or react in the formulation. Ions, for example, are commonly provided to a formulation in the form of a salt, which may dissolve and disassociate in aqueous solution. It is understood that the invention encompasses both the mixture of described ingredients and the product thus obtained.
It is understood that all ingredients in the compositions described herein are safe and palatable in the relevant concentrations for oral administration as a mouthwash.
As described in the Examples, chlorhexidine lauryl sulfate (CHX-LS) is synthesized and characterized via 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 comprises a 1:2 stoichiometric ratio of chlorhexidine cation [C22H30 Cl2N10]2+ to dodecyl sulfate anion [C12H25SO4]−. CHX-LS exhibits broad-spectrum antibacterial activity and demonstrates superior efficacy to reduce bacteria generated volatile sulfur compounds (VSCs) as compared to chlorhexidine gluconate (CHG). Surprisingly, whereas anionic surfactants such as sodium lauryl sulfate can interfere with the activity of CHX, providing the CHX in a stable complex with lauryl sulfate appears to enhance its activity.
The disclosure provides in one embodiment, a solid salt of chlorhexidine lauryl sulfate (Compound 1). For example, the disclosure provides:
In another embodiment, the disclosure provides an oral care composition (Composition 1) comprising chlorhexidine lauryl sulfate wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:4 to 1:1, e.g., approximately 1:2. For example, the disclosure provides:
In a further embodiment, the disclosure provides
For example, in one embodiment of any of the foregoing methods for treating gingivitis, prophylaxis of dental plaque and caries, treating yeast infections of the mouth, protecting against infections following oral surgery and tooth extraction, and/or reducing halitosis, the oral care composition, e.g., according to any of Compositions 1, et seq., is a mouthwash, which may be administered to the subject in need thereof twice daily by rinsing for approximately 30 seconds, morning and evening after tooth brushing, in a dosage of about 15 ml of undiluted mouthwash. The patient should be instructed to not rinse with water, or other mouthwashes, brush teeth, or eat immediately after using the mouthwash. The mouthwash is not intended for ingestion and should be expectorated after rinsing.
In a further embodiment, the disclosure provides a disinfectant composition (Composition 2) comprising chlorhexidine lauryl sulfate, water, and alcohol (e.g., ethanol, isopropyl alcohol, and mixtures thereof), for example a composition comprising 1% to 5% chlorhexidine lauryl sulfate, 65% to 80% isopropyl alcohol, and water, wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:4 to 1:1, e.g., approximately 1:2; for example wherein the chlorhexidine lauryl sulfate is according to any of Compound 1, et seq., e.g., wherein Composition 2 is formed by mixing any of Compound 1, et seq. with water and other excipients, e.g., for use as a skin disinfectant before surgery, sterilization of surgical or dental instruments, cleaning wounds, and/or for keeping urinary catheters from blocking.
In a further embodiment, the disclosure provides a method of skin disinfection before surgery comprising administering to the skin of a patient in need thereof a liquid composition comprising water and chlorhexidine lauryl sulfate wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:4 to 1:1, e.g., approximately 1:2, e.g., according to any of Composition 2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients.
In a further embodiment, the disclosure provides a method of treating or inhibiting topical infections of the skin comprising administering to the skin of a patient in need thereof, a composition (e.g., a liquid or cream) comprising water and chlorhexidine lauryl sulfate wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:4 to 1:1, e.g., approximately 1:2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients, e.g., according to any of Composition 2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients.
In a further embodiment, the disclosure provides a method for sterilization of surgical or dental instruments, 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 1:4 to 1:1, e.g., approximately 1:2, e.g., according to Composition 2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients.
In a further embodiment, the disclosure provides a method for cleaning wounds, 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 1:4 to 1:1, e.g., approximately 1:2, e.g., according to any of Composition 2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients.
In a further embodiment, the disclosure provides a method for keeping urinary catheters from blocking, comprising rinsing the catheter with a liquid composition comprising water and chlorhexidine lauryl sulfate wherein the molar ratio between chlorhexidine (CHX) and lauryl sulfate (LS) is 1:4 to 1:1, e.g., approximately 1:2, e.g., according to any of Composition 2, e.g., wherein the composition is formed by mixing any of Compound 1, et seq. with water and other excipients.
In a further embodiment, the disclosure provides a method of stabilizing chlorhexidine in an aqueous formulation, e.g., in a composition according to any of Composition 1, et seq., or Composition 2, comprising adding the chlorhexidine to the solution in the form of a solid salt of chlorhexidine lauryl sulfate, e.g., in the form of any of Compound 1, et seq.
As used herein, an “oral care composition” such as the mouthwashes and toothpastes of the disclosure refers to a composition for which the intended use includes oral care, oral hygiene, and/or oral appearance, or for which the intended method of use comprises administration to the oral cavity and refers to compositions that are palatable and safe for topical administration to the oral cavity, and for providing a benefit to the teeth and/or oral cavity. The term “oral care composition” thus specifically excludes compositions which are highly toxic, unpalatable, or otherwise unsuitable for administration to the oral cavity. In some embodiments, an oral care composition is not intentionally swallowed, but is rather retained in the oral cavity for a time sufficient to affect the intended utility. The oral care compositions as disclosed herein may be used in nonhuman mammals such as companion animals (e.g., dogs and cats), as well as by humans. In some embodiments, the oral care compositions as disclosed herein are used by humans. In some embodiments, the disclosure provides mouthwash formulations. In some embodiments, the disclosure provides toothpaste formulations.
As used herein, “nonionic surfactant” generally refers to compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in nature. Examples of suitable nonionic surfactants include poloxamers (sold under trade name PLURONIC¬Æ), polyoxyethylene, polyoxyethylene sorbitan esters (sold under trade name TWEENS¬Æ), Polyoxyl 40 hydrogenated castor oil, fatty alcohol ethoxylates, polyethylene oxide condensates of alkyl phenols, products derived from the condensation of ethylene oxide with the reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, alkyl polyglycosides (for example, fatty alcohol ethers of polyglycosides, such as fatty alcohol ethers of polyglucosides, e.g., decyl, lauryl, capryl, caprylyl, myristyl, stearyl and other ethers of glucose and polyglucoside polymers, including mixed ethers such as capryl/caprylyl (C8-10) glucoside, coco (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 materials.
In some embodiments, the nonionic surfactant comprises amine oxides, fatty acid amides, ethoxylated fatty alcohols, block copolymers of polyethylene glycol and polypropylene glycol, glycerol alkyl esters, polyoxyethytene glycol octylphenol ethers, sorbitan alkyl esters, polyoxyethylene glycol sorbitan alkyl esters, and mixtures thereof. Examples of amine oxides include, but are not limited to, laurylamidopropyl dimethylamine oxide, myristylamidopropyl dimethylamine oxide, and mixtures thereof. Examples of fatty acid amides include, but are not limited to, cocomonoethanolamide, lauramide monoethanolamide, cocodiethanolamide, 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 laurylamidopropyl dimethylamine oxide and myristylamidopropyl dimethylamine oxide. In certain embodiments, the nonionic surfactant is a combination of lauryl/myristylamidopropyl dimethylamine oxide and cocomonoethanolamide. In certain embodiments, the nonionic surfactant is present in an amount of 0.01 to 5.0%, 0.1 to 2.0%, 0.1 to 0.6%, 0.2 to 0.4%, about 0.2%, or about 0.5%.
Mouthwashes frequently contain significant levels of ethanol, which is often needed to solubilize essential oils and to prevent bacterial contamination. High levels of ethanol may be undesirable, because in addition to the potential for abuse by ingestion, the ethanol may exacerbate conditions like xerostomia. Accordingly, in some embodiments, the oral care compositions of the invention are substantially free of ethanol, e.g., contain less than 1% ethanol.
Humectants can enhance the viscosity, mouthfeel, and sweetness of the product, and may also help preserve the product from degradation or microbial contamination. Suitable humectants include edible polyhydric alcohols such as glycerin, sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of these humectants. Sorbitol may in some cases be provided as a hydrogenated starch hydrolysate in syrup form, which comprises primarily sorbitol (the product if the starch were completely hydrolyzed to glucose, then hydrogenated), but due to incomplete hydrolysis and/or presence of saccharides other than glucose, may also include other sugar alcohols such mannitol, maltitol, and longer chain hydrogenated saccharides, and these other sugar alcohols also function as humectants in this case. In some embodiments, humectants are present at levels of 5% to 25%, e.g., 15% to 20% by weight.
Flavorings for use in the present invention may include extracts or oils from flavorful plants such as peppermint, spearmint, cinnamon, wintergreen, and combinations thereof, cooling agents such as menthol, methyl salicylate, and commercially available products such as OptaCool from Symrise, as well as sweeteners, which may include polyols (which also function as humectants), saccharin, acesulfame, aspartame, neotame, stevia and sucralose.
Toothpastes, including abrasive gels, in accordance with the disclosure may comprise one or more abrasives, e.g., silica abrasives or calcium abrasives, e.g., calcium carbonate dicalcium phosphate, or calcium pyrophosphate. For example, toothpaste compositions disclosed herein may include silica abrasives, and may comprise additional abrasives, e.g., a calcium phosphate abrasive, e.g., tricalcium phosphate (Ca3(PO4)2), hydroxyapatite (Ca10(PO4)6(OH)2), or dicalcium phosphate dihydrate (CaHPO4·2H2O, also sometimes referred as DiCal) or calcium pyrophosphate; calcium carbonate abrasive; or abrasives such as sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite or other siliceous materials, or combinations thereof. These abrasives, generally have an average particle size ranging between about 1 and about 30 microns, about between 5 and about 15 microns. These particulate silica abrasives are distinct from colloidal silica thickeners.
Toothpastes in accordance with the disclosure may further comprise an anticalculus (tartar control) agent. Suitable anticalculus agents include without limitation phosphates and polyphosphates (for example pyrophosphates), polyaminopropanesulfonic acid (AMPS), hexametaphosphate salts, zinc citrate trihydrate, polypeptides, polyolefin sulfonates, polyolefin phosphates, diphosphonates. The invention thus may comprise phosphate salts. In particular embodiments, these salts are alkali phosphate salts, i.e., salts of alkali metal hydroxides or alkaline earth hydroxides, for example, sodium, potassium or calcium salts. “Phosphate” as used herein encompasses orally acceptable mono- and polyphosphates, for example, P1-6 phosphates, for example monomeric phosphates such as monobasic, dibasic or tribasic phosphate; dimeric phosphates such as pyrophosphates; and multimeric phosphates, e.g., sodium hexametaphosphate. In particular examples, the selected phosphate is selected from alkali dibasic phosphate and alkali pyrophosphate salts, e.g., selected from sodium phosphate dibasic, potassium phosphate dibasic, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any of two or more of these. In a particular embodiment, for example the compositions comprise a mixture of tetrasodium pyrophosphate (Na4P2O7), calcium pyrophosphate (Ca2P2O7), and sodium phosphate dibasic (Na2HPO4), e.g., in amounts of ca. 3-4% of the sodium phosphate dibasic and ca. 0.2-1% of each of the pyrophosphates. In another embodiment, the compositions comprise a mixture of tetrasodium pyrophosphate (TSPP) and sodium tripolyphosphate (STPP)(Na5P3O10), e.g., in proportions of TSPP at about 1-2% and STPP at about 7% to about 10%. Such phosphates are provided in an amount effective to reduce erosion of the enamel, to aid in cleaning the teeth, and/or to reduce tartar buildup on the teeth, for example in an amount of 2-20%, e.g., ca. 5-15%, by weight of the composition.
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 to form a gel. Such additional polymers include polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum), and polyvinyl pyrrolidone. Acidic polymers, for example polyacrylate gels, may be provided in the form of their free acids or partially or fully neutralized water soluble alkali metal (e.g., potassium and sodium) or ammonium salts. Silica thickeners, which form polymeric structures or gels in aqueous media, may be present. Note that these silica thickeners are physically and functionally distinct from the particulate silica abrasives also present in some compositions, as the silica thickeners are very finely divided and provide little or no abrasive action. Other thickening agents 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 arabic, and gum tragacanth can also be incorporated. Colloidal magnesium aluminum silicate can also be used as component of the thickening composition to further improve the composition's texture. In certain embodiments, thickening agents in an amount of 0.5% to 5.0% by weight of the total composition are used.
Other ingredients which may optionally be included in compositions according to the present invention include hyaluronic acid, green tea, ginger, sea salt, coconut oil, turmeric, white turmeric (white curcumin), grape seed oil, ginseng, monk fruit, vitamin E, basil, chamomile, pomegranate, aloe vera, and charcoal. Any of such ingredients may be present in an amount from 0.01% to 2% by weight of the composition, e.g., 0.01 to 1%, or 0.01 to 0.5%, or 0.01 to 0.1%.
As used herein, “orally acceptable” refers to a material that is safe and palatable at the relevant concentrations for use in an oral care formulation, such as a mouthwash.
Unless stated otherwise, all percentages of composition components given in this specification are by weight based on a total composition or formulation weight of 100%.
It is understood that, in certain cases, an ingredient may perform multiple functions. For example, polyethylene glycol may affect the viscosity of the product, but may also act as a humectant.
The compositions and formulations as provided herein are described and claimed with reference to their ingredients, as is usual in the art. As would be evident to one skilled in the art, the ingredients may in some instances react with one another, so that the true composition of the final formulation may not correspond exactly to the ingredients listed. Thus, it should be understood that the invention extends to the product of the combination of the listed ingredients.
As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls.
(HG and CHG-SLS mixture aging study: 2 gram of 20% CHG solution is used as control and SLS is added in a 1:2 molar of SLS:CHG into another 2 gram of 20% CHG solution. Both aqueous solutions are placed in a 60° C.oven and aged for 3 and 6 weeks.
Sample preparation for CHX degradation analysis by using GCMS analysis: Both aged solutions are taken from the 60° C.oven. They are diluted at 1:3.5 ratios with methanol. Both solutions are filtrated with a 0.20 um PTFE filter, respectively, then they are diluted again at a 1:10 dilution ratio with methanol and then transferred into a ROBO autosampler vials for GC-MS analysis. The gas chromatography system 6890N with 5972 MS detector plus Gerstel MPS-2 autosampler (Agilenet Technologies, Santa, Clara, CA, USA) is used for detection of CHX degradation products. Separation is accomplished using GC column of HP-5MS (30 m×0.25 mm×0.25 um, length×inside diameter×film thickness, Agilent Technologies). The 1 μL sample is injected with the splitless mode. The oven temperature is initially held at 80° C.for 1 min. Thereafter the temperature is raised at 6° C./min until 300° C.and held for 2.33 min. Total running time is 40 minutes. Helium is used as the carrier gas and delivered at a constant flow rate at 1 mL/min (the pressure at 9.38 psi and velocity at 37 cm/sec). The injector temperature is set at 250° C. and the interface temperature between GC oven and MS detector is250° C. The MS detectors are tuned with the standard spectrum autotune, and the MS data (total ion chromatogram, TIC) are acquired with the full scan mode (m/z of 45-550 at a scan rate of 3 scan/sec using the electron ionization (EI) mode with an electron energy of 70 eV. The MS source temperature is 230° C. and quat temperature is 150° C.
The relative degradation content from CHG-SLS aged at 60° C. in 3 weeks is only 4% of that seen in the CHG solution control. Even aged at 60° ° C.for 6 weeks, the degradation content in CHG-SLS mixture solutions is only about 21% relative the CHG placebo solution. Those results clearly indicated SLS can protect CHX degradation. At same time, a novel CHX-LS complex crystal is obtained from the CHG-SLS mixture.
NMR experiment: The crystal sample is fully dissolved in deuterated DMSO and prepared at 0.1 wt %. 1H NMR spectra are conducted using Bruker spectrometer operating at proton frequency of 500.13 MHz equipped with a double resonance cryoprobe. The sample temperatures are controlled at 25° C. The spectrum is collected using a single pulse with a 30° ° C. pulse angle, 1 second acquisition time, 5 second recycle delay, and a sweep width of 12 ppm. The number of scans is 32, required ˜10 min for each spectral collection. The 1H NMR spectral signals (
X-Ray experiment: Chlorhexidine lauryl sulfate (CHX-LS), comprising of chlorhexidine and sodium lauryl sulfate (sometimes referred to as sodium dodecyl sulfate) is synthesized and characterized via single crystal X-ray diffraction measurements indicating a stoichiometry of [C22H32N10Cl2]·[(C12H25O4S)2], wherein the molecules are arranged in a 1:2 ratio, with a doubly protonated chlorhexidine cation and two dodecyl sulfate anions.
Crystals of CHX-LS suitable for X-ray crystallography are isolated under the microscope and the X-ray diffraction data are collected using Bruker D8 Venture PHOTON 100 CMOS system equipped with a Cu Kα INCOATEC ImuS micro-focus source (λ=1.54178 Å). The data is collected at 100 K. Indexing is performed using APEX3 (Difference Vectors method). Data integration and reduction are performed using SaintPlus 6.01. Absorption correction is performed by multi-scan method implemented in SADABS. Space group is determined using XPREP implemented in APEX3. The structure is solved using SHELXT (direct methods) and is refined using SHELXL-2017 (full-matrix least-squares on F2) through OLEX2 interface program. All non-hydrogen atoms are refined anisotropically. Hydrogen atoms are placed in geometrically calculated positions and are included in the refinement process using riding model. Putative 3D structures of the crystal are depicted in
To further confirm the formation of the CHX-DS complex, the crystal is dissolved in methanol and analyzed by NMR and MS. Additionally, SC-XRD analysis is carried out at 100 K showing that the coordination complex CHX-DS crystallizes in triclinic P1 space group with the unit cell parameters a=11.63(3) Å; b=13.63(3) Å; c=9.14(3) Å, and α=70.24(10°); β=92.95(10°); γ=89.76(2)°. The structural formula can be described as [C22H32N10Cl2]·[(C12H25O4S)2] with the asymmetric unit consisting of one molecule of doubly protonated chlorhexidine cation and two molecules of dodecyl sulfate anion. The structure comprises one CHX molecule surrounded by two DS molecules, whereby the biguanidine moieties of the CHX are symmetrically protonated by hydrogen transfer from the acidic sulfate group of the two DS molecules. These biguanidine moieties display a delocalization of the single and double bonds, as evident from the C—N bond lengths (1.313 to 1.357 Å). The CHX dications adopt a spiral conformation giving rise to U-shaped coils extending parallel to the a-axis. The CHX cations among the coils between the adjacent layers along the c-axis are anti to each other, giving rise to alternating layers of the CHX coils that are further involved in hydrogen bonding interactions to the sulfate anions of the DS molecules with one of the DS molecules being disordered. Each of the CHX cations is involved in hydrogen bonding interactions with the sulfate groups from three different DS molecules. Two sulfate groups form two hydrogen bonds with the biguanide groups on the outer periphery, and one sulfate forms three hydrogen bonds with the inner —NH and —NH2 groups of the biguanide moieties. The H-bonding ranges from 2.057 to 2.254 Å, indicating strong hydrogen bonding.42 The PXRD pattern calculated from the single crystal structure also matches quite well with the one obtained from the bulk sample, indicating bulk phase purity.
FTIR experimental results: The CHX-LS crystal is analyzed in FTIR spectrum. The peaks around 1400˜1800 cm−1 are very similar to the SLS standard in red. The peaks around 800˜1300 cm−1 and 2000˜3000 cm−1 match the CHX standard. Therefore, the crystal contains both CHX and LS components.
Infrared spectra are collected using a Bruker Vertex 70 FTIR spectrometer (Bruker Optics, Billerica, MA) equipped with a GladiATR diamond ATR accessory (Pike technologies, Madison, WI). The spectra are acquired with a 4 cm−1 resolution in the 80-4000 cm-1 spectral range. All measurements were carried out at room temperature.
The FTIR absorption spectrum of the CHX-DS (or CHX-LS) crystal prepared in this work in comparison to those of the reference materials of SDS (sodium dodecyl sulfate, also sometimes referred to as sodium lauryl sulfate or SLS) and CHG (chlorhexidine gluconate) is shown in
LC-MS analytical results: The acquired crystal is dissolved in methanol solvent and is injected to a Thermo Q Exactive hybrid Quadrupole-Orbitrap Mass Spectrometer instrument. The analyst CHX-LS solution is delivered with the mobile phase containing 50% MeOH-water solvent. MS detector is run in the positive mode. The peak at 505 m/z indicates pure chlorhexidine having the chlorine isotope pattern. It also gives the complexes formed between chlorhexidine with LS at 771 and 1059, corresponding to CHX-LS at 1:1 and 1:2 molar ratios, respectively. The MS of pure chlorhexidine and 1:1 ratio of chlorhexidine complex could come from 1:2 ratio of chlorhexidine fragmentation.
One proposed structure of the CHX-LS is Structure A
Alternatively, the sulfate moieties may pair with the same guanidinium group, as depicted in
A series of experiments testing the molar ratios of CHG: SLS required for formation of the CHX-LS complex. It is found that the CHX-LS complex prepared from CHG and SLS forms only at specific ratios of CHG:SLS, generally a molar ratio of at least 1:4 (≥0.25), e.g., 1:1 or 1:2, at a concentration of 0.12 wt % CHG. Where the amount of CHG relative to SLS is lower, e.g., at molar ratios of CHX:LS 1:5 or less (≤0.2), no detectable salt or precipitate is formed.
Existing oral care products generally use a very low CHG:SLS ratio. For example, CHG is typically used at 0.12% by weight while SLS is used at >1% by weight. A solution of 0.12% CHG by weight and 1% SLS by weight would have a molar ratio of CHG to SLS of only about 0.03, far less than the 0.25 or greater CHX/SLS molar ratio needed to form a precipitate starting with an aqueous solution of 0.12% CHG. Therefore, it is not expected that a solid salt precipitate would exist in such products.
In vitro efficacy of chlorhexidine lauryl sulfate (CHX-LS) on reduction of volatile sulfur compounds (VSCs) is investigated using methyl mercaptan as the model sulfur compound. It is determined that CHX-LS exhibits superior antibacterial efficacy as compared to chlorhexidine gluconate (CHG) and greater reduction in volatile sulfur compounds (VSCs).
Clear solutions are prepared and used as precursors without purification. 10 wt. % and 20 wt. % solutions are prepared using sodium lauryl sulfate (SLS) and chlorhexidine gluconate (CHG), respectively, in absolute methanol. Both samples are sonicated to ensure complete dissolution. Sodium lauryl sulfate solution is added dropwise to the CHG solution. A crystalline “snow-flake” appearing material is formed after several minutes.
Methyl mercaptan (CH3SH, CAS #74-93-1) is a representative ingredient of volatile sulfur compound (VSC), which can be used as the marker for the quantitative measurement of mouth odor through gas chromatography-flame photometric detector technology. Sample preparation entails dissolution of the CHX-LS, SLS, CHX-HCl, and powders to a final concentration of 0.01 wt. %; additionally 0.01 wt. % of CHG solution is also prepared. Hydroxyapatite (HAP) is incubated with whole saliva to develop pellicles followed by the treatment of testing and control dentifrice slurries. After rinsing, the treated disks are transferred to headspace vials and incubated with VSC solution to mimic mouth odor (VSC) generation. The methyl mercaptan in headspace is measured through gas chromatography-flame photometric detector, and the results determine the product efficacy in mouth odor reduction.
The effect of CHX-LS, CHG, CHX-HCl, SLS, and methanol on in vitro bacteria-generated volatile sulfur compounds (VSC), conducted by methyl mercaptan gas chromatography (GC) headspace measurement, is illustrated in
This study shows that CHX-LS exhibits superior VSC reduction efficacy as compared to CHG. These data indicate CHX-LS is a viable and effective antimicrobial agent for malodor reduction in dentifrices and oral rinses.
While the disclosure has been described with respect to specific examples including presently preferred modes of carrying out the disclosure, those skilled in the art will appreciate that there are numerous variations and permutations of the above-described systems and techniques. It is to 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.
| Number | Date | Country | |
|---|---|---|---|
| 63430609 | Dec 2022 | US |
