Antimicrobial compositions, including chlorhexidine

Abstract

Antimicrobial composition, comprising: Chlorhexidine; a chlorhexidine-soluble solvent, wherein the chlorhexidine-soluble solvent is a solvent in which chlorhexidine is substantially soluble at 23 °C; a chlorhexidine-insoluble solvent, wherein the chlorhexidine-insoluble solvent is a solvent in which chlorhexidine is essentially insoluble at 23 °C, and wherein the chlorhexidine-insoluble solvent comprises at least 35% by weight of the antimicrobial composition; a chelating agent, wherein the chelating agent is selected from the group consisting of glutamic acid N,N-diacetic acid, methylglycine N,N-diacetic acid, glucoheptonic acid, ethanolyl diglycic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(2-hydroxyethyl)ethylenediamine N,N',N'-triacetic acid trisodium salt, disodium ethylenediaminetetraacetic acid or combinations thereof.

Description

BACKGROUND

[0001] It is common practice to disinfect the skin before invasive procedures such as surgery, catheterization, or needle insertion to reduce the risk of infection. Currently, chlorhexidine formulations are the agent of choice for disinfecting hands, skin, surgical sites, catheter sites, and the oral cavity. Chlorhexidine and its salts are well-known antimicrobials with excellent efficacy and are safe to use. Chlorhexidine and its salts also exhibit a persistent antimicrobial effect on the skin, often lasting more than 24 hours. SUMMARY OF THE INVENTION

[0002] Chlorhexidine gluconate is a commonly used disinfectant that is soluble in aqueous solutions. Because it is a common disinfectant, chlorhexidine gluconate is often used in low C2-C5 alcoholic solvents, but chlorhexidine gluconate is insoluble in C2-C5 alcoholic solvents. Furthermore, a chlorhexidine gluconate-containing solution may be susceptible to spontaneous calcium gluconate crystallization when formulated with high levels of solvents such as alcohol. These calcium gluconate crystals resemble broken glass. It is desirable to inhibit the formation of these crystals without compromising the antimicrobial efficacy of the solution. The chlorhexidine antimicrobial composition disclosed herein includes a chelating agent to inhibit the formation of this salt or to reverse crystal formation.

[0003] According to the invention, there is provided an antimicrobial composition comprising: chlorhexidine; a chlorhexidine-soluble solvent, wherein the chlorhexidine-soluble solvent is a solvent in which chlorhexidine is substantially soluble at 23°C; a chlorhexidine-insoluble solvent, wherein the chlorhexidine-insoluble solvent is a solvent in which chlorhexidine is substantially insoluble at 23°C; wherein the chlorhexidine-insoluble solvent comprises at least 35% by weight of the antimicrobial composition; and a chelating agent, wherein the chelating agent is selected from the group consisting of glutamic acid-N,N-diacetic acid, methylglycine-N,N-diacetic acid, glucoheptonic acid, ethanoldiglycic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium salt, disodium ethylenediaminetetraacetic acid, or combinations thereof.

[0004] In one embodiment, the chlorhexidine is selected from the group consisting of chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dimethosulfate, chlorhexidine dilactate, chlorhexidine diglucoheptonate, chlorhexidine diglycolate, salts, and combinations thereof. In one embodiment, the chlorhexidine is present in an amount of at least 0.05% by weight based on the total weight of the composition.

[0005] In one embodiment, the chlorhexidine-soluble solvent comprises water. In one embodiment, the proportion of the chlorhexidine-soluble solvent in the antimicrobial composition is at least 15% by weight. In one embodiment, the proportion of the chlorhexidine-soluble solvent in the antimicrobial composition is less than 25% by weight.

[0006] In one embodiment, the chlorhexidine-insoluble solvent comprises a C2-C5 lower alcohol as the solvent. In one embodiment, the chlorhexidine-insoluble solvent comprises a hydrophobic polymer that is soluble or dispersible in the lower alcohol. In one embodiment, the hydrophobic polymer is selected from the group consisting of acrylates and their derivatives, cellulose and its derivatives, n-vinyllactam copolymers, and vinyl copolymers, as well as combinations of two or more of the foregoing. In one embodiment, the hydrophobic polymer is present in the antimicrobial composition in an amount of at least 2% by weight based on the total weight of the antimicrobial composition. In one embodiment, the chlorhexidine-insoluble solvent is at least 60% by weight of the antimicrobial composition.In one embodiment, the proportion of the chlorhexidine-insoluble solvent in the antimicrobial composition is less than 80% by weight. In one embodiment, the chlorhexidine-soluble solvent comprises less than 25% by weight and the chlorhexidine-insoluble solvent comprises at least 75% by weight of the antimicrobial composition.

[0007] In one embodiment, the chelating agent is soluble in the chlorhexidine-soluble solvent. In one embodiment, the chelating agent is soluble in the chlorhexidine-insoluble solvent. In one embodiment, the chelating agent has a formation constant with calcium of at least 10 6at neutral pH. In one embodiment, the chelating agent is present in the antimicrobial solution at between 10 ppm and 10,000 ppm. In one embodiment, the chelating agent is present in the antimicrobial solution at less than 100 ppm. In one embodiment, the chelating agent removes or prevents the crystallization of at least one of aluminum, barium, iron, calcium, copper, cobalt, cadmium, mercury, magnesium, manganese, nickel, lead, and strontium ions.

[0008] In one embodiment, the antimicrobial composition further comprises an emollient. In one embodiment, the emollient is an emollient ester. In one embodiment, the emollient ester is selected from the group consisting of diesters of bibasic acids, triesters of citric acid, diesters of diols, triesters of triols, and combinations thereof.

[0009] In one embodiment, the antimicrobial composition is applied to a surface and dried on the surface. Definitions

[0010] “Ambient temperature,” as used herein, refers to the temperature range between approximately 21°C and 25°C.

[0011] “Chlorhexidine-soluble solvent,” as used herein, means a solvent in which chlorhexidine is substantially soluble at 23°C.

[0012] “Chlorhexidine-insoluble solvent,” as used herein, means a solvent in which chlorhexidine is substantially insoluble at 23°C.

[0013] "Cidatrope," as used herein, is a term for a hydrophobic component in the composition that enhances the effectiveness of the antimicrobial composition such that, when the composition without the antimicrobial agent and the composition without the cidatrope component are used separately, they do not provide the same level of antimicrobial activity as the composition as a whole. For example, a cidatrope component may not provide appreciable antimicrobial activity in the absence of the antimicrobial agent. The enhancing effect may relate to the level of killing, the rate of killing, and / or the spectrum of microorganisms killed and may not be observed for all microorganisms.The cidatrope component can be a synergist such that, when combined with the rest of the composition, the composition as a whole exhibits activity greater than the sum of the activity of the composition without the cidatrope component and the composition without the antimicrobial agent. Typically, the cidatrope is liquid at ambient conditions and has a melting temperature of less than 25°C. If more than one cidatrope is present in the antimicrobial composition, at least one cidatrope has a melting temperature of less than 25°C. The hydrophobic polymer, the plasticizer esters, and the optional fatty component all function as cidatrope components in the compositions described herein.

[0014] “Copolymer” includes a polymer of any length (including oligomers) made from two or more types of polymerizable monomers, including terpolymers, tetrapolymers, etc., which may include random copolymers, block copolymers, or sequential copolymers.

[0015] "Emollient," as used herein, refers to materials capable of maintaining or improving the level of moisture, compliance, or appearance of the skin with repeated application. Emollients often increase the moisture content of the stratum corneum. Emollients are generally divided into two broad classes based on their function. The first class of emollients works by forming an occlusive barrier that reduces water evaporation from the stratum corneum. The first class of emollients is further divided into compounds that are waxes at room temperature and compounds that are liquid or oils. The second class of emollients penetrates the stratum corneum and physically binds water to prevent evaporation. Included in the second class of emollients are water-soluble emollients, often referred to as humectants.The emollient esters are considered separately from any other emollients that may be used, although the emollient esters may act as occlusive emollients and may contribute to maintaining or improving the condition of the skin.

[0016] “Substantially free” means less than 1 wt%, in one embodiment less than 0.5 wt%, and in one embodiment less than 0.1 wt% of a component based on the total weight of the composition.

[0017] “Fat,” as used herein, refers to a hydrocarbon chain length of 8 or more carbon atoms (odd or even number), unless otherwise specified.

[0018] “Hydrophobic” or “water-insoluble” refers to a material that does not dissolve significantly in water at 23°C.

[0019] “Hydrophobic polymers” as disclosed have a solubility in water of less than 1%, in one embodiment less than 0.5%, in one embodiment less than 0.25%, and in one embodiment less than 0.10%.

[0020] "Hydrophilic" or "water-soluble" or "water-swellable" refers to a material that dissolves, solubilizes, disperses, or otherwise suspends in water (or another aqueous solution, as specified) at a temperature of 23°C in an amount of at least 7% by weight, in one embodiment at least 10% by weight, in one embodiment at least 20% by weight, in one embodiment at least 25% by weight, in one embodiment at least 30% by weight, and in one embodiment at least 40% by weight, based on the total weight of the hydrophilic material and water. The component is considered dissolved when, after thorough mixing with water at 60°C for at least 4 hours and after cooling to 23-25°C for 24 hours and thoroughly mixing the composition in a 4 cm path length glass, it exhibits a uniform clear solution with no visible turbidity, phase separation, or precipitation.Typically, the sample, when placed in a 1 x 1 cm cell, exhibits a transmittance of greater than 70%, measured in a suitable spectrophotometer at a wavelength of 655 nm. Water-dispersible hydrophilic materials disperse in water, forming uniform, cloudy dispersions upon vigorous shaking of a 5% by weight mixture of the hydrophilic component in water. Water-swellable hydrophilic materials dissolve or suspend in water, including those materials that form a viscous solution or gel.

[0021] “Lotion” is a liquid or creamy substance that does not contain a propellant.

[0022] “(Meth)acrylate monomers” are acrylic acid esters or methacrylic acid esters of alcohols.

[0023] “Non-volatile” means that the component does not evaporate easily under ambient conditions, so that a 20 g sample in a 4 cm 2large shell does not lose more than 2% of its weight, e.g., within 60 minutes when exposed to ambient conditions. Examples of non-volatile components of the compositions described herein include glycerin, chlorhexidine and its salts, and fatty components with a chain length of more than 10 carbons.

[0024] “Polymer,” as used herein, refers to a natural or synthetic molecule having repeating units and a number average molecular weight of at least 10,000 and includes homopolymers and copolymers of any length.

[0025] Solubility can be determined by thoroughly mixing the compound with the solvent at the appropriate concentration at 23°C for at least 24 hours (or at elevated temperature if necessary to dissolve the compound), then allowing it to stand at 23-25°C for 24 hours and observing the sample. In a glass vessel with a path length of 4 cm, the sample should show evidence of a second phase, which may be liquid or solid and may be distributed at the top, bottom, or throughout the sample. For crystalline compounds, care should be taken to avoid producing a supersaturated solution. The components should be mixed and observed. Turbidity or the presence of a visible precipitate or separate phase indicates that the solubility limit has been exceeded.Typically, the sample has a transmittance of less than 70% in a 1 x 1 cm cell, measured with a suitable spectrophotometer at a wavelength of 655 nm. For solubility determinations below the solubility observable with the naked eye, the solubility is determined using radiolabeled compounds, as described in "Conventional Solubility Estimations in Solubility of Long-Chain Fatty Acids in Phosphate Buffer at pH 7.4," Henrik Vorum, et al., in Biochimica et al. Biophysica Acta, 1126, 135-142 (1992).

[0026] “Solvent,” as used herein, refers to any compound used to dissolve or disperse another compound.

[0027] “Solvent system” or “hydroalcoholic solvent system,” as used herein, refers to the combination of the chlorhexidine-soluble solvent and the chlorhexidine-insoluble solvent in the compositions described herein.

[0028] “Surfactant,” as used herein, is synonymous with “emulsifier” and means an amphiphile (a molecule that has both polar and nonpolar regions that are covalently bonded) that can reduce the surface tension of water and / or the interfacial tension between water and an immiscible liquid. DETAILED DESCRIPTION

[0029] The compositions provided herein comprise chlorhexidine and a chlorhexidine-soluble solvent, as well as a chlorhexidine-insoluble solvent. Chlorhexidine has limited solubility in alcoholic solutions. In some embodiments, relatively high alcohol concentrations are desirable. In some embodiments, the alcohol solutions further comprise additional components, such as hydrophobic polymers and plasticizers, so that a chlorhexidine-containing film forms upon drying. The addition of polymers and plasticizers further increases the concentration of the chlorhexidine-insoluble solvent. If the concentration of the chlorhexidine-insoluble solvent is at least 35% by weight of the total composition, spontaneous formation of crystals from the chlorhexidine, which appear like glass or small needles, may occur over time.The compositions provided herein further comprise a chelating agent selected from the group consisting of glutamic acid-N,N-diacetic acid, methylglycine-N,N-diacetic acid, glucoheptonic acid, ethanoldiglycic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium salt, disodium ethylenediaminetetraacetic acid, or combinations thereof. The addition of a small amount of a chelating agent can completely reverse crystal formation and dissolve the crystal through highly effective and specific chelation or prevent crystal formation. Chlorhexidine

[0030] Chlorhexidine is the component of the composition that provides at least some of the antimicrobial activity. Chlorhexidine includes chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dimethosulfate, chlorhexidine dilactate, chlorhexidine diglucoheptonate, chlorhexidine diglycolate, salts, and combinations thereof.

[0031] Based on the total weight of the antimicrobial composition, the chlorhexidine can be used at a level of at least 0.05 wt.%, in one embodiment at least 0.1 wt.%, in one embodiment at least 0.25 wt.%, and in one embodiment at least 0.5 wt.%. Compounds of this class are typically used at levels of less than about 8 wt.%, in one embodiment less than about 6 wt.%, and in one embodiment less than about 4 wt.% of the composition.

[0032] Chlorhexidine can be used as a free base or as a disalt of acetate, gluconate, lactate, methosulfate (CH3OSO3 - ) or a halide, or combinations thereof. A commonly used chlorhexidine is chlorhexidine digluconate (CHG).

[0033] When formulating chlorhexidine, care must also be taken to ensure that it is not inactivated by sequestration in micelles that may form upon incorporation of surfactants and / or emulsifiers. Typically, the compositions are essentially free of surfactants and / or emulsifiers.

[0034] Chlorhexidine is very basic and capable of forming multiple ionic bonds with anionic materials. For this reason, chlorhexidine-containing compositions are typically free of anionic compounds that can lead to precipitation of the antimicrobial agent. Anionic surfactants, which may be used, for example, as wetting agents, should also be avoided. Halide salts may need to be avoided. For example, chlorhexidine digluconate (CHG) rapidly precipitates in the presence of halide salts above a concentration of approximately 0.1 M. Therefore, when a system includes CHG and must include salts for stability or other reasons, gluconate salts such as triethanolamine gluconate or sodium gluconate are used. Chlorhexidine soluble solvent

[0035] The chlorhexidine-soluble solvent can be any solvent in which chlorhexidine is substantially soluble. In one embodiment, the chlorhexidine-soluble solvent is water. As the chlorhexidine-insoluble solvent increases, the chlorhexidine-soluble solvent decreases. In some embodiments, the proportion of chlorhexidine-soluble solvent to the total composition is at least 15% by weight. In some embodiments, the proportion of chlorhexidine-soluble solvent is less than 25% by weight of the total composition. Chlorhexidine insoluble solvent

[0036] The chlorhexidine-insoluble solvent can be any solvent in which the chlorhexidine is essentially insoluble. In one embodiment, the chlorhexidine-insoluble solvent is a C2-C5 alcohol. The alcohol can be selected from ethanol and isopropanol. Ethanol has a broad spectrum and rapidly kills microbes and has an odor that is acceptable to consumers such as physicians, nurses, and clinicians. Propyl alcohols (1-propanol and 2-propanol) can also be used.

[0037] A mixture of two or more lower alcohols can be used as the chlorhexidine-insoluble solvent in the hydroalcoholic solvent system. The lower alcohols can be denatured, such as denatured ethanol, including SDA-3C (commercially available from Eastman Chemical, Kingsport, TN). Furthermore, co-solvents can be included in the composition with the lower alcohol. Given the topical application contemplated for the antimicrobial composition, suitable co-solvents include acetone, hydrocarbons such as isooctane, glycols, ketones, ethers, and short-chain esters.

[0038] When a hydrophobic polymer or plasticizer is included as part of the chlorhexidine-insoluble solvent, the lower C2-C5 alcohol used in the compositions is used in sufficient amount to dissolve the hydrophobic polymer and the emollient ester.

[0039] In one embodiment, the chlorhexidine-insoluble solvent is present in an amount of at least 35% by weight of the total composition. In one embodiment, the chlorhexidine-insoluble solvent is present in an amount of at least 60% by weight of the total composition. In one embodiment, the chlorhexidine-insoluble solvent is present in an amount of at least 80% by weight of the total composition.

[0040] Compositions having a higher alcohol-to-water ratio in the range of 40:60 to 95:5 ensure effective, immediate killing of bacteria. In one embodiment, the higher alcohol:water ratio is between about 55:45 and 90:10, and in one embodiment, at least 65:35. In one embodiment, a higher alcohol:water ratio is used to achieve optimal antimicrobial effect and to ensure that the composition dries quickly.

[0041] The appropriate concentration of the hydrophobic polymer and the antimicrobial agent depends on their respective solubility in a particular hydroalcoholic solvent system. For example, the solubility of CHG in the hydroalcoholic solvent system decreases with increasing C2-C5 alcohol concentration. In contrast, for the hydrophobic polymers, an increased level of C2-C5 alcohol concentration may be required to solubilize the hydrophobic polymers. One of ordinary skill in the art can readily determine an optimal concentration range for a particular antimicrobial composition or solvent system based on the solubility of the cationic antimicrobial agent and the hydrophobic polymer. Chelating agents

[0042] The antimicrobial composition comprises a chelating agent. In one embodiment, the chelating agent is soluble in the chlorhexidine-soluble solvent. In one embodiment, the chelating agent is soluble in the chlorhexidine-insoluble solvent. In one embodiment, the chelating agent has a formation constant with calcium of at least 10 6 at a neutral pH. In one embodiment, the chelating agent is present in the antimicrobial solution at between 10 and 10,000 ppm of the total composition. In one embodiment, the chelating agent is present in the antimicrobial solution at less than 100 ppm.

[0043] The chelating agent is selected from the group consisting of glutamic acid-N,N-diacetic acid, methylglycine-N,N-diacetic acid, glucoheptonic acid, ethanoldiglycic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, (N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium salt (trisodium HEDTA), disodium ethylenediaminetetraacetic acid, or combinations thereof. The chelating agent removes or prevents the crystallization of at least one of the ions aluminum, barium, iron, calcium, copper, cobalt, cadmium, mercury, magnesium, manganese, nickel, lead, and strontium.

[0044] Antimicrobial compositions comprising chlorhexidine, chlorhexidine-soluble solvent, and chlorhexidine-insoluble solvent comprising at least 35% by weight of the antimicrobial composition, with the chelator, demonstrated effective reduction of crystals.

[0045] In one embodiment, the formation constant for the HEDTA complex with calcium at neutral pH is 10 6 , and this high affinity causes a remarkable reversal of calcium gluconate crystal formation at extremely low application levels, as can be seen in the accompanying figures. Optional hydrophobic polymers

[0046] The antimicrobial composition may include a hydrophobic polymer soluble in the chlorhexidine-insoluble solvent and a plasticizer, such as an emollient ester, to provide enhanced antimicrobial efficacy to the antimicrobial composition. In certain embodiments, the hydrophobic polymers have a water solubility of less than 1%, in one embodiment less than 0.5%, in one embodiment less than 0.25%, and in one embodiment less than 0.10%. The films formed after the antimicrobial composition dries adhere well to the skin, remain flexible and do not tear when the skin is slightly flexed, and do not wash off when contacted with water or body fluids.

[0047] Hydrophobic polymers suitable for use in the antimicrobial compositions include film-forming polymers derived from n-vinyllactam, such as those described in U.S. Patent Nos. 4,542,012 and 4,584,192; vinyl polymers as described in U.S. Patent No. 7,030,203; and cellulose, including its derivatives (except those that are hydrophilic, water-soluble, or water-swellable), such as ethylcellulose.

[0048] Suitable hydrophobic polymers include film-forming polymers that are the reaction product of a prepolymer having a plurality of isocyanate functionalities and a polyvinylpyrrolidone polymer. The polyvinylpyrrolidone polymer is a reaction product of the free radical polymerization of at least N-vinylpyrrolidone and a vinyl-functional compound, as further described in U.S. Patent No. 4,542,012. Other suitable film-forming polymers include film-forming copolymers comprising (i) a monomeric acrylic or methacrylic acid ester of an alkyl alcohol having from 2 to about 14 carbon atoms containing a single hydroxyl, (ii) a monomeric methacrylic acid ester of an alkyl alcohol having from 1 to 6 carbon atoms containing a single hydroxyl, and (iii) an N-vinyllactam, as further described in U.S. Patent No. 4,584,192.

[0049] Other suitable hydrophobic polymers include vinyl polymers, for example, polymers derived from vinyl monomers such as (meth)acrylates, (meth)acrylamides, vinyl ethers, vinyl acetates, and their hydrolyzed derivatives, styrenic compounds (i.e., derivatives of styrene), and N-vinyllactams (e.g., N-vinylpyrrolidone, N-vinylcaprolactam, and their derivatives). Suitable vinyl polymers are soluble (i.e., they form transparent, homogeneous solutions) or dispersible in the lower alcohol and are rather insoluble or sparingly soluble in water. Certain vinyl polymers containing combinations of three monomers (terpolymers) are also useful.

[0050] One class of polymers useful in the antimicrobial compositions described herein includes polymers derived from the polymerization of at least one monoethylenically unsaturated alkyl (meth)acrylic monomer, preferably an alkyl (meth)acrylic acid ester (i.e., an alkyl acrylate or alkyl methacrylate). One class of vinyl polymers contains at least one copolymerized monoethylenically unsaturated alkyl (meth)acrylic monomer. As used herein, the term "monoethylenically unsaturated" in the alkyl (meth)acrylic monomer refers to the acrylic unsaturation. "Alkyl (meth)acrylic" monomers include (meth)acrylamides (e.g., octylacrylamide), (meth)acrylates, and combinations thereof. The alkyl (meth)acrylic monomer is an alkyl (meth)acrylic acid ester (i.e., an alkyl acrylate or alkyl methacrylate) wherein the alkyl group has (on average) at least 4 carbon atoms.

[0051] Examples of monomers that can be used to prepare the hydrophobic polymer include, but are not limited to: vinylpyridine, methyl acrylate, ethyl acrylate, butyl acrylate, ethylhexyl acrylate, isooctyl acrylate, isoamyl acrylate, isobornyl acrylate, isotetradecyl acrylate, lauryl acrylate, stearyl acrylate, behenyl acrylate, ethylhexyl diglycol acrylate, 2-hydroxy-3-phenoxypropyl acrylate, hydroxybutyl acrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, butoxyethyl acrylate, ethoxydiethylene glycol acrylate, hexyl polyethylene glycol acrylate, methoxytriethylene glycol acrylate, phenoxyethyl acrylate, phenoxypolyethylene glycol acrylate, tetrahydrofurfuryl acrylate, glycidyl methacrylate, trimethylpropane benzoate acrylate, methyl methacrylate, ethyl methacrylate, butyl methacrylate, octadecyl acrylate, Hydroxypropyl methacrylate, hydroxyethyl methacrylate, vinyl acetate, N-vinylpyrrolidone, N-vinyl lactams, styrene, styrene macromer, vinyl butyral, acrylamide, dimethylaminoethyl methacrylate, dimethylaminoethyl acrylate,Diethylaminoethylstyrene, diethylaminoethyl methacrylate, butylaminoethyl methacrylate, aminoethyl methacrylate hydrochloride, diisopropylaminoethyl methacrylate, morpholinoethyl acrylate, morpholinoethyl methacrylate, dimethylaminoneopentyl acrylate, diallylamine, aminoethyl methacrylamide, aminopropyl methacrylamide, dimethylaminopropylacrylamide, dimethylaminopropyl methacrylamide, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylamide, and their quaternary salts such as dimethylaminoethyl acrylate methyl chloride, diallyldimethylammonium chloride, aminopropyl methacrylamide hydrochloride, and aminoethyl methacrylamide hydrochloride. The hydrophobic polymer formed by the polymerization of at least one of these monomers can be a homopolymer, copolymer, terpolymer, or a mixture of polymers.

[0052] Other suitable hydrophobic polymers include cellulose and its hydrophobic derivatives, for example methyl, ethyl, propyl and butyl, optionally including hydroxyl, methoxy, ethoxy, propoxy and butoxy groups, as well as C5-C 20 -Alkyl derivatives and derivatives that are a combination thereof. Some examples of such cellulose derivatives include methylhydroxypropylcellulose, cetylhydroxyethylcellulose, hydroxypropylcellulose, ethylhydroxyethylcellulose, ethylcellulose, hydroxymethylcellulose, and hydroxybutylmethylcellulose. In one embodiment, the cellulose derivative is ethylcellulose.

[0053] Hydrophobic polymers useful in the antimicrobial compositions described herein are soluble in the hydroalcoholic solvent system, and particularly in the chlorhexidine-insoluble solvent, such as a lower alcohol. Generally, the hydrophobic polymers used herein are insoluble or only slightly soluble in water. When used alone, the hydrophobic polymers may be capable of forming water-resistant films. Such polymers are desirable in the antimicrobial compositions described herein because they would create, for example, surgical hand preparations and antimicrobial hand lotions that cannot be easily washed off with water after application and drying.

[0054] The hydrophobic polymer of the composition, together with the plasticizer, for example, an emollient ester, and optionally the fatty component, can also contribute to improved adhesion of medical adhesive devices to the skin, particularly in the presence of moisture or fluids. The hydrophobic polymer can also be liquid to improve the overall cosmetic skin feel of the composition.

[0055] The hydrophobic polymers are typically not ethoxylated. Ethoxylation affects the moisture sensitivity of the resulting antimicrobial composition, leading to a reduction in adhesion. If one of the components is ethoxylated, it usually involves no more than one or two moles of ethylene oxide.

[0056] When used, the hydrophobic polymer is present in the composition in an amount of at least 0.1 wt.%, in one embodiment at least 1 wt.%, in one embodiment at least 3 wt.%, and in one embodiment at least 5 wt.% based on the total weight of the antimicrobial composition. In certain embodiments, the hydrophobic polymer is present in amounts of no more than 10 wt.%, and in one embodiment no more than 6 wt.%. Optional plasticizer

[0057] When the antimicrobial composition includes a hydrophobic polymer, a plasticizer is typically included to provide enhanced antimicrobial efficacy to the antimicrobial composition. In one embodiment, the plasticizer is an emollient ester, such as a cidatrope, which provides enhanced antimicrobial efficacy to the antimicrobial composition. In one embodiment, the emollient ester comprises at least 8 carbon atoms in total. In one embodiment, the emollient ester comprises no more than 20 carbon atoms. In one embodiment, the emollient ester comprises at least two ester bonds.

[0058] The emollient esters can serve to prevent skin irritation and dryness, improve the cosmetic product, enhance the antimicrobial activity of the formulation, and moisturize the skin by reducing water permeability. In higher concentrations, the emollient esters also enhance the dry adhesion of medical adhesives.

[0059] The emollient ester is generally liquid at room temperature and has low water solubility, meaning it is soluble in water at 23°C in amounts of less than 2% by weight. Emollient esters suitable for use as cidatropes in antimicrobial compositions are selected from diesters of bibasic acids, diesters of diols, triesters of citric acid, triesters of triols, and combinations thereof.

[0060] In certain embodiments, the emollient ester is selected from the group consisting of (C1-C8) alkyl alcohol esters of (C2-C12) diacids, for example, dibutyl adipate, diisopropyl adipate, diisobutyl adipate, dihexyl adipate, diisopropyl sebacate, and dibutyl sebacate; diesters of butanediol and hexanediol; propylene glycol dicaprylate; (C2-C8) alkyl alcohol di- and triesters of citric acid, for example, tributyl citrate; and combinations thereof. Other emollient esters include dialkyl acid esters of diols, triesters of citric acid and trialkyl acid esters of triols, as well as dialky alcohol esters of other di- and tricarboxylic acids.

[0061] In certain embodiments, the emollient ester is selected from the group consisting of dialkyl esters of bibasic acids, trialkyl esters of citric acid, dialkyl esters of diols, trialkyl esters of triols, and combinations thereof. Diesters of bibasic acids include dibutyl adipate, diisopropyl adipate, diisobutyl adipate, dihexyl adipate, diisopropyl sebacate, dibutyl sebacate, and mixtures thereof. Similarly, triesters of citric acid include tributyl citrate. Diesters of diols include esters of butanediol and hexanediol. Diesters of propylene glycol, such as propylene glycol dicaprylate, may also be useful. Typical emollient esters are diisopropyl adipate, dibutyl adipate, and tributyl citrate.

[0062] Examples of other suitable emollient esters include, but are not limited to: short chain (i.e., C1-C6) alkyl or (C6-C12) aryl esters of long (i.e., C8-C36) straight or branched chain alkyl or alkenyl alcohols or acids; short chain (i.e., C1-C6) alkyl or (C6-C12) aryl esters of (C4-C12) diacids or (C4-C12) diols optionally substituted in available positions by -OH; (C2-C18) alkyl or (C6-C12) aryl esters of glycerin, pentaerythritol, ethylene glycol, propylene glycol; (C12-C22) alkyl esters or (C12-C22) ethers of polypropylene glycol; (C12-C22) alkyl esters or (C12-C22) ethers of polypropylene glycol / polyethylene glycol copolymers; and long-chain (i.e., C8-C36) alkyl and alkenyl esters of long (i.e., C8-C18) straight-chain or branched alkyl or alkenyl alcohols or acids, long-chain (i.e., C8-C36) alkyl and alkenyl amides of long straight-chain or branched (i.e., C8-C36) alkyl or alkenyl amines or acids.

[0063] In certain embodiments, the emollient ester is selected from the group consisting of (C1-C6) alkyl and (C6-C12) aryl esters of straight-chain or branched (C8-C36) alkyl or alkenyl alcohols or acids; (C1-C6) alkyl and (C6-C12) aryl diesters of (C2-C12) diacids or (C4-C12) diols, optionally positioned in at least one available position by -OH; (C1-C6) alkyl and (C6-C12) aryl di- or tri-esters of citric acid, (C2-C18) alkyl and (C6-C12) aryl esters of glycerin, pentaerythritol, ethylene glycol or propylene glycol; (C12-C22) alkyl esters and (C12-C22) ethers of polypropylene glycol; (C12-C22) alkyl esters and (C12-C22) ethers of polypropylene glycol / polyethylene glycol copolymer; long-chain (i.e. C8-C36) alkyl and alkenyl esters of long (i.e. C8-C18) straight-chain or branched alkyl or alkenyl alcohols or acids, long-chain (i.e. C8-C36) alkyl and alkenyl amides of long straight-chain or branched (i.e.C8-C36) alkyl or alkenyl amines or acids.

[0064] In certain embodiments, the emollient ester is selected from the group consisting of (C1-C6) alkyl and (C6-C12) aryl esters of straight-chain or branched (C8-C36) alkyl or alkenyl alcohols or acids; (C1-C6) alkyl and (C6-C12) aryl diesters of (C2-C12) diacids or (C4-C12) diols, optionally positioned in at least one available position by -OH; and (C1-C6) alkyl and (C6-C12) aryl di- or triesters of citric acid.

[0065] In one embodiment, the emollient ester is present in the composition in an amount of at least 0.1 wt.%, in one embodiment, at least 1 wt.%, and in one embodiment, at least 2 wt.%. In some embodiments, the emollient ester is present in amounts of no more than 10.0 wt.%, in one embodiment, no more than 6 wt. Higher levels may also be used depending on the ratio of the cationic antimicrobial agent to the total non-volatile components (see above). Optional fat component

[0066] The antimicrobial composition may optionally also include a fatty component that provides enhanced antimicrobial efficacy of the antimicrobial composition. Fatty components include a C 12 -C 21 -fatty alcohol, a C 12 -C 21 -fatty acid esters with one or more free hydroxyl groups, a C 12 -C 21-fatty ethers with one or more free hydroxyl groups, a C 12 -C 21 -fatty amide with one or more free hydroxyl groups, and combinations thereof. The fatty component of the composition, together with the hydrophobic polymer and the emollient ester, can also contribute to improved adhesion of medical adhesive devices to the skin, particularly in the presence of moisture or fluids. The fatty component can also be waxy to improve the overall cosmetic skin feel of the composition.

[0067] The fatty components are typically not ethoxylated. Ethoxylation affects the moisture sensitivity of the resulting antimicrobial composition, leading to a reduction in adhesive strength. If any of the components are ethoxylated, it usually involves no more than one or two moles of ethylene oxide.

[0068] When used, the fatty component is present in the composition in an amount of at least 0.5 wt%, in one embodiment at least 1 wt%, in one embodiment at least 2 wt%, and in one embodiment at least 3 wt% based on the total weight of the antimicrobial composition. In certain embodiments, the fatty component is present in amounts of no more than 6 wt%, and in some embodiments no more than 5 wt%. Additional optional ingredients

[0069] The compositions may optionally include ingredients such as salts, humectants (in minimal amounts due to their hydrophilic nature and their influence on moisture sensitivity), stabilizers, other antimicrobials, fragrances, therapeutic agents, propellants, dyes, solvents, other emollients, conditioning agents, and vitamins. Hydrophilic surfactants and other additives may optionally be added to the antimicrobial composition. Typically, the formulations are substantially free of surfactants. In one embodiment, the compositions are substantially free of hydrophilic polymers and water-soluble or water-swellable polymers. Use of the wording

[0070] The antimicrobial compositions are suitable for preoperative surgical, catheter-based, and IV skin antiseptic preparation, for hand antiseptics, and surgical scrubs. The antimicrobial compositions can be useful for preventing or reducing catheter-related bloodstream infections. The compositions can be used to prevent surgical site infections by applying the compositions to the skin prior to surgery. These compositions can be used to reduce temporary and normal skin flora. Repeated applications can be used to provide even greater efficacy on the skin.

[0071] The compositions can be applied using a variety of techniques, including, but not limited to, foam applicators, cotton swabs, saturated swabs, saturated wipes, aerosols, sprays, brushes, and dips. The compositions can be applied to the skin or an inanimate object for 15 to 180 seconds and then allowed to dry. The compositions are suitable for infection prevention products, such as preoperative antiseptic surgical preparations and antiseptic skin preparations used before catheterization. These compositions are useful when used in conjunction with medical adhesives, tapes, surgical drapes, and transparent dressings under moist or suboptimal conditions.

[0072] Because the compositions contain antimicrobial agents, it is important that they be dosed in an effective and precise amount. The compositions can be dispensed in a discrete, substantially uniform amount using the dispensers disclosed in U.S. Patent No. 5,897,031 and U.S. Patent No. 5,799,841.

[0073] Although specific embodiments have been illustrated and described herein, it should be understood that these embodiments are merely exemplary of the many possible specific arrangements that may be devised using the principles of the invention. Numerous and varied other arrangements may be devised by those skilled in the art in accordance with these principles without departing from the spirit and scope of the invention. The scope of the present invention should not be limited to the structures described in this application, but only to the structures described in the claims and the equivalents of those structures. Examples

[0074] The chemicals used were procured as follows: 20% CHG solution: Medichem SA, Carrer de Fructuös Gelabert, 6, 08970 Sant Joan Despí, Barcelona, ​​Spain Isopropanol: Sigma-Aldrich Company, 4353 E 49th St, Cleveland, OH 44125, USA Acetyl tributyl citrate: Sigma-Aldrich Company, 4353 E 49th St, Cleveland, OH 44125, USA Ethocel-20 polymer: Dow Chemical Company, Midland, MI 48674, USA N-(2-Hydroxyethyl)ethylenediaminetriacetic acid trisodium salt: Sigma-Aldrich Company, 4353 E 49th St, Cleveland, OH 44125, USA Source material:

[0075] For testing, three hydroalcoholic samples of chlorhexidine gluconate were prepared with different amounts (in grams) of excipients. The composition of the three samples is shown below: Component (g) A B C 20% CHG solution 6,1 6,1 6,1 Water 7,5 5,8 5,8 Isopropanol 36,4 32,1 32,1 Acetyltributyl citrate 0 6 3 Ethocel-20 polymer 0 0 3

[0076] All three samples were clear and free of particles after preparation. The samples were stored at room temperature for 60 days. After approximately 30 days, tiny needle-shaped calcium gluconate crystals were observed in all three solutions. The number of crystals initially increased but soon reached a visually observed equilibrium state, indicating the presence of a limited amount of calcium in the CHG solution. Example 1:

[0077] The three samples from Example 1 were treated with different levels of N-(2-hydroethyl)ethylenediaminetriacetic acid trisodium salt (HEDTA.Na3) (which has a calcium formation constant of more than 10^10) and stirred for three days. The solutions were then analyzed for their crystal content. The results are shown below: sample 12.5 ppm (mg / kg) HEDTA.Na3 25 ppm (mg / kg) HEDTA.Na3 50 ppm (mg / kg) HEDTA.Na3 100 ppm (mg / kg) HEDTA.Na3 A Crystals No crystals No crystals No crystals B Crystals Crystals Crystals No crystals C Crystals Crystals Crystals No crystals Example 2:

[0078] The calcium chelating agent's formation constant affects its ability to reduce the formation of calcium crystals. Two well-known chelating agents with relatively low calcium formation constants, namely citric acid (CA) (which has a calcium formation constant of 10^3.24) and sodium pyrophosphate (SP) (which has a calcium formation constant of 10^4.95), were used instead of HEDTA.Na3 in the above example and compared with HEDTA.Na3. sample 100 ppm CA 200 ppm CA 100 ppm SP 200 ppm SP 100 ppm HEDTA.Na3 A Crystals Crystals Crystals Crystals No crystals B Crystals Crystals Crystals Crystals No crystals C Crystals Crystals Crystals Crystals No crystals QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] US 4,542,012 [0047, 0048] US 4,584,192 [0047, 0048] US 7,030,203

[0047] US 5,799,841

[0072] Zitierte Nicht-Patentliteratur

[0000] Conventional Solubility Estimations in Solubility of Long-Chain Fatty Acids in Phosphate Buffer at pH 7.4“, Henrik Vorum, et al. in Biochimica et. Biophysica Acta, 1126, 135-142 (1992

[0025]

Claims

[1] Antimicrobial composition comprising: Chlorhexidine; a chlorhexidine-soluble solvent, wherein the chlorhexidine-soluble solvent is a solvent in which chlorhexidine is substantially soluble at 23°C; a chlorhexidine-insoluble solvent, wherein the chlorhexidine-insoluble solvent is a solvent in which chlorhexidine is substantially insoluble at 23°C, wherein the chlorhexidine-insoluble solvent comprises at least 35% by weight of the antimicrobial composition; a chelating agent, wherein the chelating agent is selected from the group consisting of glutamic acid-N,N-diacetic acid, methylglycine-N,N-diacetic acid, glucoheptonic acid, ethanoldiglycic acid, diethylenetriaminepentaacetic acid, nitrilotriacetic acid, N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium salt, disodium ethylenediaminetetraacetic acid, or combinations thereof. [2] The antimicrobial composition of claim 1, wherein the chlorhexidine is selected from the group consisting of chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dimethosulfate, chlorhexidine dilactate, chlorhexidine diglucoheptonate, chlorhexidine diglycolate, salts, and combinations thereof. [3] The antimicrobial composition of claim 2, wherein the chlorhexidine is chlorhexidine digluconate. [4] An antimicrobial composition according to any one of the preceding claims, wherein the chlorhexidine is present in an amount of at least 0.05% by weight based on the total weight of the composition. [5] An antimicrobial composition according to any preceding claim, wherein the chlorhexidine-soluble solvent constitutes less than 25% by weight of the antimicrobial composition. [6] An antimicrobial composition according to any preceding claim, wherein the chlorhexidine-soluble solvent comprises water. [7] An antimicrobial composition according to any preceding claim, wherein the chlorhexidine-insoluble solvent comprises a C2-C5 lower alcohol. [8] The antimicrobial composition of claim 7, wherein the chlorhexidine-insoluble solvent comprises a hydrophobic polymer that is soluble or dispersible in the lower alcohol. [9] The antimicrobial composition of claim 8, wherein the hydrophobic polymer is selected from the group consisting of acrylates and their derivatives, cellulose and its derivatives, n-vinyllactam copolymers and vinyl copolymers, and combinations of two or more of the foregoing. [10] The antimicrobial composition of claim 8 or 9, wherein the hydrophobic polymer is present in the antimicrobial composition in an amount of at least 2% by weight based on the total weight of the antimicrobial composition. [11] The antimicrobial composition according to any one of the preceding claims, wherein the chlorhexidine-insoluble solvent constitutes at least 60% by weight of the antimicrobial composition. [12] An antimicrobial composition according to any preceding claim, wherein the chlorhexidine-insoluble solvent constitutes less than 80% by weight of the antimicrobial composition. [13] An antimicrobial composition according to any preceding claim, wherein the chlorhexidine-soluble solvent comprises less than 25% by weight and the chlorhexidine-insoluble solvent comprises at least 75% by weight of the antimicrobial composition. [14] An antimicrobial composition according to any preceding claim, wherein the chelating agent is soluble in the chlorhexidine-soluble solvent and / or in the chlorhexidine-insoluble solvent. [15] An antimicrobial composition according to any one of the preceding claims, wherein the chelating agent has a formation constant with calcium of at least 10 6 at neutral pH. [16] An antimicrobial composition according to any preceding claim, wherein the chelating agent is present in the antimicrobial solution at between 10 and 10,000 ppm of the total composition. [17] The antimicrobial composition of claim 16, wherein the chelating agent is present in the antimicrobial solution at less than 100 ppm. [18] An antimicrobial composition according to any preceding claim, wherein the chelating agent is N-(2-hydroxyethyl)ethylenediamine-N,N',N'-triacetic acid trisodium salt. [19] An antimicrobial composition according to any preceding claim, further comprising a plasticizer. [20] The antimicrobial composition of claim 19, wherein the plasticizer is an emollient ester.