Antimicrobial cleansing agent

Abstract

To provide a novel composition for skin cleansing.SOLUTION: An antimicrobial cleansing agent for skin comprises a solution having an effective solute level of at least 2.0 Osm / L and a pH value of from 3.5 to 5.5, a) the solvent component of the solution comprising water and at least one glycol, and b) the solute component of the solution comprising at least 1 wt.% of one or more anionic surfactants, a dissociation product of a polyacid, and a dissociation product of the salt of the polyacid.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This international application claims priority to U.S. Provisional Patent Application No. 61 / 818,586, filed on May 2, 2013, and U.S. Provisional Patent Application No. 61 / 873,500, filed on September 4, 2013. Both applications are hereby incorporated by reference in their entirety.

[0002] Background Bacteria are the cause of a significant amount of disease and infection. Removing bacteria from surfaces is desirable to reduce human exposure. Since bacteria express self - preservation mechanisms, it is very difficult to remove and / or eradicate them.

[0003] Bacteria can be found in several forms, such as planktonic organisms or biofilms. In biofilms, bacteria interact with surfaces and form colonies. The colonies adhere to the surface and continue to grow. Bacteria produce exopolysaccharide (EPS) and / or extracellular - polysaccharide (ECPS) macromolecules. These cross - link to form a matrix or film that aids in the attachment of bacteria to the surface.

[0004] In addition to adhering to surfaces, the biofilm matrix protects bacteria from many forms of attack. The protection includes both the small diameter of the flow channels in the matrix that limit the size of molecules that can be transported to the underlying bacteria, and the consumption of biocides by interaction with the constituent EPS and / or ECPS macromolecules.

[0005] Furthermore, bacteria in biofilms are down-regulated (sessile) and do not divide actively. This makes them resistant to most attacks by antibacterial agents that attack bacteria during their active life stages, such as during cell division.

[0006] Due to the macromolecular matrix or the protection conferred by their down-regulation, bacteria in biofilms are very difficult to treat. The types of biocides and germicides effective for treating this form of bacteria are strongly acidic, oxidizing, and toxic, and often contain halogen atoms, oxygen atoms, or both. Common examples include concentrated bleach, strong inorganic acids (such as HCl), high-concentration quaternary ammonia compounds and aldehydes, and hydrogen peroxide. Generally, the administration of such chemicals is allowed to contact the biofilm or spores for a long time (up to 24 hours in some situations). This is impractical for many applications.

[0007] Formulations that disrupt or bypass the macromolecular matrix and / or disable the natural defenses of these matrices are described in U.S. Patent Application Nos. 2010 / 0086576 and 2012 / 0059263. These formulations contain an acid or base, buffer salts added at a sufficient concentration to provide relatively high permeability, and a large amount of surfactant, along with solutes that create a difference in osmotic pressure inside and outside the bacterial cell wall, and surfactants that weaken their walls through interaction with wall proteins, and are aqueous compositions.

[0008] The above compositions do not usually immediately break down the biofilm macromolecular matrix. Instead, they convert the matrix into a gel-like state while still providing some shielding for the bacteria. The overall efficacy and bactericidal rate of these compositions are limited by the rate of flux of the active ingredient moving through the biofilm matrix and the rate of bacterial cell wall degradation. (The disintegration of EPS reduces the mean free path that the antibacterial component must travel.)

[0009] Furthermore, regulatory authorities (the US Food and Drug Administration and the Environmental Protection Agency) have set threshold amounts for surfactants such as benzalkonium chloride and cetylpyridinium chloride. All compositions containing such surfactants in amounts greater than their respective thresholds must be investigated for safety prior to commercial introduction for specific uses. Such uses include, but are not limited to, for example, items that come into contact with food (items that are not rinsed), oral rinses, medical device sterilants, and items that come into contact with the skin. The foregoing compositions typically have surfactant concentrations that exceed the normally prescribed threshold amounts.

[0010] Summary Even when the composition is at or near neutral pH, an antibacterial composition effective against various states of bacteria is provided. The composition according to the present invention is lethal against a broad spectrum of Gram-positive and Gram-negative bacteria and exhibits lethality against microorganisms such as viruses, fungi, molds, yeasts, and bacterial spores. In many embodiments, the composition has little or no toxicity to humans and animals.

[0011] The antibacterial composition includes a solvent component and a solute component, and the solute component is present in an amount sufficient for the overall osmolality of the composition to be at least 500, typically at least 575, and generally at least 650 mOsm / L. The solvent component includes one or more organic liquids selected such that the δp value, which is the dipolar intermolecular force (polarity) Hansen solubility parameter (HSP), is about 15.1 or less.

[0012] The high osmolality of the composition combined with the correct solubility parameter can solvate the macromolecular matrix of the biofilm and bacterial cell wall proteins quickly, even in the absence of surfactant. Solvent components showing the required δp values were found to solubilize microbial cell wall proteins even better and more efficiently. By making some portions of these cell wall proteins go into solution, the entrained bacteria may more readily cause cell leakage, which, combined with the high partial pressure inside and outside the cell wall, leads to the death of the bacteria. Furthermore, improving the dissolution of the macromolecular matrix and increasing its solubility in the solvent system allows for a shorter mean free path for the active ingredients (chemicals interacting with the bacteria), thereby increasing their speed and density and reducing their required contact time and / or stringency. These advantages allow for the use of the composition at lower total component concentrations and / or milder use conditions (e.g., pH).

[0013] Compositions with a near-neutral pH are effective, but the pH of the composition is typically slightly low (about 4 ≤ pH ≤ 6) or slightly high (about 8 ≤ pH ≤ 10). Higher or lower pH values can enhance the effect, perhaps by reacting with or forming complexes with cross-linking metal ions, or by enabling the composition to more efficiently break apart the macromolecular matrix of the biofilm.

[0014] At least some of the osmotic active solutes may contain dissociation products of one or more acids or bases effective to disrupt or break the ionic cross-links in the macromolecular matrix of the biofilm. This facilitates the passage of the solutes, and, if used, the surfactant, through the matrix in which the bacteria are entrapped and / or by which they are protected.

[0015] Furthermore, methods of using the foregoing compositions are provided. In a typical method, a composition of the type described above can be applied to a biofilm to achieve at least a 3-log reduction in the number of viable bacteria. For example, application of the composition of the present invention to a biofilm tested according to the Center for Disease Control (CDC) biofilm reactor test method described below can provide at least a 3-log reduction in the number of viable bacteria after a 5-minute residence time.

[0016] Furthermore, methods of making the compositions are provided. In a typical method, a target δp value is specified, and one or more solvents having a δp value within 0.5 MPa of the target value are identified and combined with a solute sufficient to provide a composition having an osmoticity of at least 500, 600, 700, or 800 mOsm / L. 1 / 2 In another typical method, an aqueous composition containing one or more solutes can be modified by the addition of one or more organic liquids to provide the composition with a target δp that is less than the δp of the original (aqueous) composition.

[0017] The composition can be incorporated into a semi-adhesive gel or an adhesive coating that allows the active ingredient to elute over time to prevent colony formation on the gel or coated surface, or can be retained within the gel or coating. In the case of a gel, the composition can use various water-miscible ointment bases and provide control over the elution rate from the gel to provide continuous application of the antibacterial composition, or provide explosive application or elution of the product to protect the surface.

[0018]

[0019] ​Sometimes, one may have a particular interest or concern in a single bacterial strain. In those cases, a composition that is particularly effective against that bacterium can be formulated based on the differences in cell wall proteins of different bacterial species. This is particularly beneficial in situations where it is desired to eliminate pathogenic bacteria without affecting the survival of the microflora. (In these cases, the promising composition will adopt a target δp that is different from the one described above. It is intended for broad-spectrum efficacy and is expected to kill all the microorganisms exposed to the composition using a composition that is polar at or near the target.)

[0020] The enhanced effectiveness of the composition allows for the use of lower concentrations of surfactant. Although not absolutely required, the presence of a surfactant (especially a polar surfactant) enhances the efficacy of these formulations and increases the rate at which the composition acts on the targeted microorganisms. This is most likely due to the surfactant causing cell lysis by contacting those portions of the cell wall proteins that become soluble by the solvent component.

[0021] Any patents and / or published patent applications mentioned as references are incorporated herein by reference.

Brief Description of the Drawings

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[0036] Detailed Description The HSP mentioned in the previous brief description is a general method for predicting whether one substance will dissolve in another to form a solution, and HSP values are most commonly used to describe solvents. (Many alternative methods for determining the solubility of a solute in a solvent are also available. The most common alternative is the Hildebrand solubility parameter. It measures the cohesive energy density of the solvent and solute and compares them for similarity. Polar forces are not separated from dispersion forces and hydrogen bonding forces. Also, for reasons that will become apparent below, it is not very desirable to use the Hildebrand solubility parameter as a measurement / selection tool. However, those skilled in the art will recognize that it can also be used in the same way as other methods to identify appropriate combinations of organic liquids and / or solvents.)

[0037] Components in a mixture or composition each have three HSPs: dispersion forces, dipole-dipole (polar) interactions, and hydrogen bonding. These parameters are generally treated as three-dimensional coordinates, along with an HSP property description visualized using polar coordinates: the 3D coordinates consist of the center of the sphere and the radius of the sphere (R 0Alternatively, it has an "interaction radius", which indicates the maximum difference in acceptable affinity for a "good" interaction with a solvent or solute. In other words, acceptable solvents are located within the interaction radius, and those that are difficult to accept are located outside it.

[0038] The so-called Hansen space (Ra), which is the distance between the HSPs of two substances, can be calculated by the following formula: (Ra) 2 = 4(δ d2 - δ dl ) 2 +(δ p2 - δ p1 ) 2 +(δ h2 - δ hl ) 2 (I) In the formula, δd is the energy from intermolecular dispersive forces, δp is the energy from dipole-dipole intermolecular forces, and δh is the energy from intermolecular hydrogen bonds.

[0039] The simple composition affinity parameter (relative energy difference (RED)) represents the ratio of the calculated HSP difference (Ra) to the interaction radius (i.e., RED = Ra / R 0 )(R 0 ). When RED < 1.0, the solubility of the molecules is sufficiently similar and one dissolves the other. When RED ≥ 1.0, the solubility of the molecules is not sufficiently similar for one to dissolve the other. When RED is approximately 1.0, partial dissolution is possible.

[0040] Regression analysis of the data collected during the development of the compositions of the present invention showed that each of the δp, δd, and Ra values is related to the effectiveness of the composition. (Due to the direct correlation among the δp, δd, and Ra values, a composition containing a solvent component with the stated δp value can also be described from the viewpoints of δd and Ra values.)

[0041] Two interesting regression analysis statistics are the F-value and the p-value. The F-value is calculated by dividing the mean square of the test factor (e.g., δp) by the mean square of the test error (unassigned variation). A higher value means that the test factor is more important than chance. (The mean square is the sum of squares divided by the degrees of freedom.) The p-value is the probability of obtaining a value greater than the test statistic when the null hypothesis is true (in this case, there is no difference between the likelihood of an effect increase by chance with or without the addition of the solvent).

[0042] Despite all of δp, δd, and Ra values being correlated with the effect of the composition, the F-value and p-value based only on the δp value have the highest correlation. Possible reasons for the dominant importance of the δp factor are that for the proteins on the surface of the cross-linked bacteria in situ, it is not relatively important for all proteins to become soluble for efficacy. That is, it is necessary to dissolve only a part of the protein arbitrarily by an acid / base and / or surfactant to cause leakage of cell contents through or across the cell membrane.

[0043] The dipole-dipole interaction Hansen solubility parameter can be calculated for a particular solution or solvent combination by the following formula:

[0044]

Equation

[0045] δdi is the energy from the dipole interaction for solvent i, xdi is the percentage of solvent i in the solvent part of the composition, and n is the total number of solvent components.

[0046] The δp value for a given solvent or solvent combination is determined at room temperature. This is because solubility typically increases with increasing temperature, so the dissolution rate of the macromolecular matrix and bacterial cell wall proteins increases, and the effect of the compositions of the present invention is expected to be greater at higher temperatures. Also, the pH value can be obtained by any of various potentiometric methods using a properly calibrated electrode.

[0047] The composition can comprise at least the following two components: a solvent having a δp value low enough to dissolve some of the bacterial cell wall proteins, and a solute capable of raising the osmoticity of the system to a level high enough to cause cell lysis. As discussed below, the efficacy of the composition can often be improved by including an amount of acid or base sufficient to change the pH from neutral and / or by including one or more types of surfactants.

[0048] The components used to prepare or provide such components, when used at concentrations commonly used commercially, typically have no effect on bacteria in the form of biofilms, but a properly formulated composition can be very effective in destroying and making the biofilm impervious, thereby causing the composition to solvate certain portions of the bacterial cell wall proteins, causing leakage of the bacterial cell membrane, resulting in cell lysis, and thereby enabling the killing of bacteria even in the attached state.

[0049] The solvent component typically comprises water (δp is approximately 16.0 MPa 1 / 2 ) and at least one organic liquid having a δp value lower than that of water.

[0050] Water is commonly used as the solvent component of the composition because of its high solute retention capacity (which allows for a more permeable composition), wetting properties, excellent biocompatibility, environmental friendliness, and low cost. In essence, it is preferred that the bacteria without pretreatment are relatively few, but any water source can be used. It is not necessary to distill or deionize the water, but such treatments are not excluded. The water can be heated to increase the solubility of one or more of the other components of the composition.

[0051] When the solvent component contains water and one or more organic liquids, the latter acts to lower the δp value of the solvent component to a point where the solvent system makes one or more of the proteins of the bacterial cell wall more soluble. In other words, the Ra of the solvent system is such that it is at most about 1.0 with respect to at least one bacterial cell wall protein. 0 It is made as follows. That is, the solvent system - protein RED is at most about 1.0.

[0052] The δp value of the solvent component as a whole is less than 16.0, generally less than about 15.8, less than about 15.6, less than about 15.4, or less than about 15.2, preferably at most about 15.1, at most about 15.0, at most about 14.8, at most about 14.6, at most about 14.4, at most about 14.2, or at most about 14.0 MPa 1 / 2 For it to be effective over a wide spectrum, the δp value of the solvent component as a whole is generally from 13.1 to 15.7 MPa 1 / 2 usually from 13.3 to 15.6 MPa 1 / 2 typically from 13.5 to 15.5 MPa 1 / 2 and most typically from 13.7 to 15.4 MPa 1 / 2 up to.

[0053] Regarding the organic liquid, the δp value is practically less than about 2, less than about 3, less than about 4, less than about 5, less than about 6, less than about 7, less than about 8, less than about 9, less than about 10, less than about 11, less than about 12, less than about 13, less than about 14, less than about 14.2, less than about 14.4, less than about 14.6, less than about 14.8, less than about 15.0, less than about 15.1, less than about 15.2, less than about 15.3, less than about 15.5 MPa 1 / 2Those can be used. Non-limiting examples of organic liquids having such δp values are provided in Tables 1 and 2 below.

[0054] When used with water, such substances are generally present at concentrations of 0.1 to about 33%, 0.25 to about 25%, 0.5 to about 20%, about 1 to about 15%, about 2 to about 12%, about 3 to about 11, about 4 to about 10% or about 5 to about 10%. All of the above expressions are w / v measurements, i.e., grams of organic liquid per liter of the total solvent component of the composition.

[0055] The amount of a given organic liquid (or mixture of organic liquids) added to water can be calculated using Equation (II) when the targeted δp value is known. Similarly, the planned δp value can be calculated using Equation (II) when the amount of organic liquid and their individual δp values are known. Methods of formulating antibacterial compositions based on both such techniques are contemplated.

[0056] The presence of water in the solvent component is preferred for the reasons explained above, but an organic liquid or a mixture of a number of organic liquids, each having a δp value of less than 15.5 MPa 1 / 2 or having an overall δp value of less than 15.5 MPa 1 / 2 and capable of solvating the solute component (and other optional components) can be used in the presence or absence of water.

[0057] The solvent component can consist of, or consist essentially of, only organic liquids. In other embodiments, the solvent component can consist of, or consist essentially of, water and an organic liquid having a δp value of less than 15.5 MPa 1 / 2 or can consist of, or consist essentially of, water and two or more organic liquids that provide a solvent composition having a δp value of less than 15.5 MPa 1 / 2

[0058] ​Regarding organic liquids, preferred compounds include ethers and alcohols due to their low tissue toxicity and environmentally friendly properties. These can be added at concentrations up to their solubility limits in the other components of the composition.

[0059] Examples of ether-based liquids that can be used among the solvent components include those defined by the following general formula: R 1 (CH 2 ) x O-R 2 -[O(CH 2 ) z y Z (II) In the formula, x is an integer from 0 to 20 (optionally 2 ≤ x ≤ 20 and including one or more ethylenic unsaturations), y is 0 or 1, z is an integer from 1 to 4, R 2 is a straight-chain or branched-chain alkylene group of C 1 -C 6 , R 1 is a methyl, isopropyl or phenyl group. Also, Z is a hydroxyl group or a methoxy group. Non-limiting examples of glycol ethers (compounds of formula (III) where Z = OH) that can be used among the solvent components are shown in Table 1.

[0060]

Table 1

[0061] Alcohols that can be used include cyclic and C 1 -C 16 acyclic (straight-chain, branched-chain, saturated or unsaturated) alcohols, optionally containing one or more ethylenic unsaturations and / or one or more heteroatoms other than alcoholic oxygen (halogen atoms, amine nitrogen, etc.). Non-limiting examples of representative examples are shown in the following table.

[0062]

Table 2

[0063] Other organic liquids may be used to achieve miscibility with water. Non-limiting examples thereof include ketones such as acetone, methyl butyl ketone, methyl ethyl ketone, chloroacetone; acetates such as amyl acetate, ethyl acetate and methyl acetate; (meth)acrylates and derivatives such as acrylamide, lauryl methacrylate and acrylonitrile; aryl compounds such as benzene, chlorobenzene, fluoro-benzene, toluene, xylene, aniline and phenol; aliphatic alkanes such as pentane, isopentane, hexane, heptane and decane; halogenated alkanes such as chloroform, methylene dichloride, chloroethane and ethylene tetrachloride; cycloalkanes such as cyclopentane and cyclohexane; and polyhydric alcohols such as ethylene glycol, diethylene glycol, propylene glycol, hexylene glycol and glycerin. When selecting such an organic liquid for use in the solvent component of the composition, it is considered to avoid those containing a functional group that reacts with either the acid / base or salts used in the composition, and it is preferred that it is within the range pre-approved by a higher level of regulation.

[0064] Adjustment of the solvent concentration and the polarity value makes it possible to target a specific species or sub-genus of bacteria. For example, pathogenic bacteria on the tissue surface are suppressing native, beneficial flora (e.g., acne treatment). When the targeted bacteria have a δp value outside the known (or determinable) broad-spectrum efficacy range, e.g., it has a δp value of 15.4, while the beneficial flora is stable in that δp value or a somewhat lower region, a composition prepared by formulating a solvent component having a δp value of 15.4 can be used to (completely or essentially) eradicate the target bacteria without killing the beneficial flora, thereby providing further advantages to the treated tissue after the pathogenic bacteria have been removed.

[0065] The solute components of the antibacterial composition will be described. The compositions of the present invention have high permeability and the effect increases with osmolality. However, in some applications where reduced permeability is required or desirable, the efficacy can be maintained at lower permeability as long as the threshold required to cause an osmotic imbalance across the bacterial cell wall is maintained. The greater presence of these solutes helps to negate the defense mechanism provided by the EPS macromolecules of the matrix; in other words, having abundant solutes ensures that, even if many are consumed by interaction with the matrix of macromolecules, a sufficient amount arrives at the associated bacteria to cause a high osmotic pressure across the bacterial cell wall membrane and lead to cell disruption.

[0066] This efficacy does not depend on the specific identity or nature of the individual compounds of the solute component. Smaller molecules are generally more effective than larger molecules due to their solubility capacity (i.e., the ability for a given amount of the solvent component to contain (typically) more smaller molecules than an equimolar amount of larger molecules), the relative ease of passing through the matrix of the biofilm macromolecules, and the ease of movement across the cell wall membrane. Charged and chelated molecules are preferred types of solutes as they increase the dissolution of the macromolecular matrix by removing cross-linking metal ions between the EPS chains.

[0067] Any of the many solutes can be used to increase the permeability of the composition. It increases the difference in osmotic pressure across the bacterial cell wall membrane.

[0068] One approach to achieving increased permeability of the composition is by adding large amounts of ionic compounds (salts); see, for example, U.S. Patent 7,090,882.

[0069] When one or more organic acids or bases are used in the composition, although not required, one preferred approach to increasing permeability is to include salts of one or more acids or bases, or salts of one or more other organic acids. For example, if the composition contains an acid, it can further contain several times the excess (e.g., 3 to 10 times, preferably at least 5 times, or at least 8 times) of one or more salts of that acid. The identity of the countercationic portion of the salt is not considered to be particularly important, and common ones such as ammonium ions and alkali metals are shown as examples. When polyacids are used, all or fewer of the H atoms of the carboxyl groups can be replaced with the same or different cationic atoms or groups. For example, mono-, di-, and trisodium citrate can be used as potentially useful buffer precursors. However, trisodium citrate has three available basic groups, so it has a theoretical buffering capacity that is up to 200% greater than that of sodium citrate (which has only one such site) and up to 50% greater than that of disodium citrate (which has two such sites).

[0070] Regardless of how it is achieved, the osmotic pressure of the composition is at least moderately high and preferably has an osmotic pressure of at least about 0.5 Osm / L for most applications. Depending on the specific end use, the composition can have any of the following concentrations: at least about 0.6, at least about 0.75, at least about 1.0, at least about 1.5, at least about 1.75, at least about 2.0, at least about 2.25, at least about 2.5, at least about 2.75, at least about 3.0, at least about 3.25 and at least about 3.5 Osm / L (the upper limit being defined by the solubility limit of the solute in the solvent component). For some applications, particularly those involving contact with human or animal tissue, relatively lower solute concentrations (e.g., 0.7 - 2.5 Osm / L, 0.8 - 2.45 Osm / L, 0.9 - 2.4 Osm / L, 0.95 - 2.35 Osm / L and 1 - 2.33 Osm / L) can typically be used. For other applications, such as those requiring the sterilization of inanimate objects, relatively higher solute concentrations (e.g., 1 - 3.6 Osm / L, 1.1 - 3.5 Osm / L, 1.2 - 3.4 Osm / L, 1.3 - 3.3 Osm / L, 1.4 - 3.2 Osm / L and 1.5 - 3.1 Osm / L) can be used. (In biological applications, for comparison, 0.9% (by weight) saline is about 0.3 Osm / L and is typically considered to have moderate osmotic power, while 3% (by weight) saline is about 0.9 Osm / L and is generally considered to have a high osmotic pressure. Without being bound by theory, compositions with higher osmotic pressure can exert a higher osmotic pressure on bacterial cell walls and increase susceptibility to disruption by solvents and / or surfactants.)

[0071] The solvent component increases the efficiency of the composition both with respect to the dissolution of the macromolecular matrix and the stimulation of cell lysis. Thus, a lower osmotic pressure composition can be formulated to provide greater efficacy than a corresponding composition that does not include the types of solvent components described above. In view of this enhanced efficiency, the values in the previous section can be reduced by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 18% or about 20%.

[0072] With respect to pH, neutral embodiments of the compositions of the present invention can be effective. These neutral pH compositions may reduce the efficacy against some bacteria compared to their lower or higher pH counterparts (although still superior to alternative techniques), but conversely are expected to be more effective for other species than their acidic or alkaline counterparts.

[0073] Generally, moving the pH of the composition away from neutral results in increased efficacy due to an increased driving force for chelation of metal ions that crosslink with the EPS polymer. To that end, the rate at which the composition disrupts (or at least softens) the matrix of macromolecules is increased, and the efficacy of bacterial cell wall disruption and attack is increased, thereby increasing the rate of cell lysis. This increase may not be linear. That is, the increase in efficacy may asymptote with respect to hydronium or hydroxide ion concentration.

[0074] In comparison to compositions with very high or very low pH values (i.e., pH greater than about 10 or less than about 4), they are not environmentally friendly or safe, but can be highly effective for some applications. For some applications where efficacy is more important than biocompatibility, the pH of the composition can be as low as about 2.0 or as high as about 12.5.

[0075] In vivo uses (including nasal irrigation) generally involve compositions having a pH of 4 ≦ pH ≦ 7. For uses on the skin, compositions having a pH of 4 ≦ pH ≦ 9.5 are generally used. When the pH of the composition is greater than about 3 or less than about 10, the composition is generally biocompatible; specifically, long-term external exposure does not give negative results to the skin. Also, ingestion is attributable to biodegradation and / or bioabsorption, especially if diluted with water immediately after ingestion. When the pH is greater than about 4 or less than about 10, accidental inhalation or contact with an aerosolized version of the composition does not result in pharyngeal convulsions or other throat-related damage. However, embodiments of compositions having a pH below about 4 or above about 10 are considered to be significantly less toxic than currently available products.

[0076] For hard surface cleaning, such as hospital and food service area disinfection uses, compositions having a pH of 4 ≦ pH ≦ 6 or 8 ≦ pH ≦ 10 are typically used. For more stringent uses, such as sterilization of medical devices and equipment, compositions having a pH of 2 ≦ pH ≦ 4 or 9 ≦ pH ≦ 12 are generally used.

[0077] From the foregoing description, it can be seen that compositions having a pH other than neutral are preferred. Preferred compositions include those having a pH value at least 0.5 unit away from neutral, those having a pH value at least 1.0 unit away from neutral, those having a pH value at least 1.5 units away from neutral, those having a pH value at least 2.0 units away from neutral, those having a pH value at least 2.5 units away from neutral, those having a pH value at least 3.0 units away from neutral, those having a pH value at least 3.5 units away from neutral, those having a pH value at least 4.0 units away from neutral, those having a pH value at least 4.5 units away from neutral.

[0078] In the acidic form of the composition of the present invention, it is generally less than 6.8, less than 6.6, less than 6.4, less than 6.2, less than 6.0, less than 5.8, less than 5.6, less than 5.4, less than 5.2, less than 5.0, less than 4.8, less than 4.6, less than 4.4, less than 4.2, less than 4.0, less than 3.8, less than 3.6, less than 3.4, less than 3.2, less than 3.0, less than 2.8, less than 2.6, less than 2.4, less than 2.2, or about 2.0. As a range, the pH can be from about 2 to about 6.7, from about 2.5 to about 6.5, from about 2.7 to about 6.3, from about 3 to about 6, from about 3.3 to about 5.7, or from about 3.5 to about 5.5.

[0079] The acidity can be achieved by adding one or more acids to the solvent component (or vice versa). Strong (mineral) acids such as HC1, H 2 SO 4 、H 3 PO 4 、HNO 3 、H 3 BO 3Alternatively, or preferably, an organic acid, particularly an organic polyacid, may be used. Examples of organic acids include monobasic acids such as formic acid, acetic acid and substituted derivatives (e.g., hydroxyacetic acid, chloroacetic acid, dichloroacetic acid, phenylacetic acid, etc.), propanoic acid and substituted derivatives (e.g., lactic acid, pyruvic acid, etc.), various benzoic acid derivatives (e.g., mandelic acid, chloromandelic acid, salicylic acid, etc.), glucuronic acid, etc.; dibasic acids such as oxalic acid and substituted derivatives (e.g., oxamic acid), butanedioic acid and substituted derivatives (e.g., malic acid, aspartic acid, tartaric acid, citramalic acid, etc.), pentanedioic acid and substituted derivatives (e.g., glutamic acid, 2-ketoglutaric acid, etc.), hexanedioic acid and substituted derivatives (e.g., mucic acid), butanedioic acid (both cis- and trans-isomers), iminodiacetic acid, etc., tribasic acids such as citric acid, 2-methylpropane-1,2,3-tricarboxylic acid, benzenetricarboxylic acid, nitrilotriacetic acid, etc.; tetrabasic acids such as pyromellitic acid, etc.; and even higher order acids such as penta-, hexa-, heptabasic acids, etc. Here, when tri-, tetra-, or higher order acids are used, one or more of the carboxyl protons can be substituted with the same or different cationic atoms or groups (e.g., alkali metal ions).

[0080] In certain embodiments, preference is given to the use of organic acids or bases that are highly soluble, or can be made highly soluble, in an aqueous system. Acids containing groups that enhance solubility in water (e.g., hydroxyl groups), such as tartaric acid, citric acid and citramalic acid, are preferably used in some situations. Examples of these bases include NaOH, Na 2 CO 3 and NH 3can be mentioned. In these and / or other embodiments, biologically compatible organic acids and bases are preferably used. Many of the organic acids and bases listed above are used for manufacturing or processing food products, personal care products, etc. Alternatively, or additionally, organic acids and bases that can act to form chelates by binding to the metal cations involved in cross-linking with the matrix of the macromolecules of the biofilm are preferably used.

[0081] In the basic form of the composition of the invention, the pH generally exceeds 7.5, generally exceeds 8.0, generally exceeds 8.4, generally exceeds 8.6, generally exceeds 9.0, generally exceeds 9.2, generally exceeds 9.4, generally exceeds 9.6, generally exceeds 9.8, generally exceeds 10.0, generally exceeds 10.2, generally exceeds 10.4, generally exceeds 10.6, generally exceeds 10.8, generally exceeds 11.0, generally exceeds 11.2, generally exceeds 11.4, generally exceeds 11.6, generally exceeds 11.8, generally exceeds 12.0, generally exceeds 12.2, generally exceeds 12.4, generally exceeds 12.5. From the perspective of the range, the pH can be about 8 to about 12.5, about 8.2 to about 12.0, about 8.4 to about 11.5, about 8.6 to about 11.0, or about 8.8 to about 10.5.

[0082] The basicity is achieved by adding one or more bases. Examples of bases include, but are not limited to, the following. Alkali metal salts of weak acids including acetate, bicarbonate, fulmates, lactate, phosphate, and glutamate; alkali metal nitrates; alkali metal hydroxides especially NaOH and KOH; alkaline earth metal hydroxides especially Mg(OH) 2 ; alkali metal borates; NH 3 ; and alkali metal hypochlorites (e.g., NaClO) and bicarbonates (e.g., NaHCO 3 ).

[0083] Can the amount of acid or base added to the solvent component be calculated, or can it be added until the composition reaches the desired pH using standard pH monitoring equipment to track increases or decreases?

[0084] In the compositions described in U.S. Patent Application Nos. 2010 / 0086576 and 2012 / 059263, it was not intended to include one or more organic liquids as part of the solvent component, and the addition of a surfactant, preferably an ionic surfactant, was required. In the compositions of the present invention, a surfactant is not necessary. The addition of a surfactant improves the ability to stabilize EPS polymers (by binding to those polymers and incorporating them into solution), aids in the extraction of proteins from bacterial cell walls, and is associated with cell leakage and cell lysis.

[0085] Essentially, any substance having surface-active properties in water can be used, regardless of whether there is water in the solvent component of the composition. Those having a certain type of ionic charge are expected to enhance antibacterial properties. This is because such a charge is thought to lead to more effective cell membrane disruption and ultimately cell leakage and cell lysis upon contact with bacteria. Since this mechanism does not involve disruption of cell processes, it can kill even adherent bacteria.

[0086] Polar surfactants are generally more effective than nonpolar surfactants. Ionic surfactants are the most effective because they can interact directly with EPS polymers and bacterial cell wall proteins. For polar surfactants, cationic surfactants are the most effective, followed by zwitterionic and anionic surfactants. Furthermore, smaller surfactants are more effective because they can move more easily through the biofilm macromolecular matrix and access the associated bacteria. Another factor affecting the efficacy of ionic surfactants is the size of the side chain groups attached to the polar head. Larger dimensions and a greater number of side chain groups attached to the polar head may decrease the efficacy of the surfactant.

[0087] Since the surfactant is not the only component in the composition of the present invention that is involved in making the protein soluble (i.e., assisting the solubilizing power in the process), nonionic surfactants can find more utility in the composition of the present invention than in conventional compositions that do not contain solvents. Bacterial cell wall proteins are already made soluble by the organic liquid in the solvent component, and nonionic surfactants are able to interact with them by lower-order mechanisms such as van der Waals forces.

[0088] Since surfactants often have advantages, they can be included in the composition even if they provide little or no improvement in the efficacy provided by the organic liquid.

[0089] Potentially useful anionic surfactants include, but are not limited to, the following. Ammonium lauryl sulfate, dioctyl sodium sulfosuccinate, perfluorobutane sulfonic acid, perfluorononanoic acid, perfluorooctane sulfonic acid, perfluorooctanoic acid, potassium lauryl sulfate, sodium dodecylbenzenesulfonate, radium lauryl sulfate, sodium lauroyl sarcosinate, sodium myreth sulfate, sodium myreth sulfate, sodium pareth sulfate, sodium stearate, sodium chenodeoxycholate, N-lauroylsarcosine sodium salt, lithium dodecyl sulfate, sodium 1-octanesulfonate, sodium cholate hydrate, sodium deoxycholate, sodium dodecyl sulfate (SDS), sodium glycodeoxycholate, sodium lauryl sulfate, and the alkyl phosphates described in U.S. Patent 6,610,314.

[0090] While not limiting, potentially useful cationic surfactants include the following. Cetyl pyridinium chloride (CPC), cetyl trimethylammonium chloride, benzethonium chloride, 5-bromo-5-nitro-1,3-dioxane, dimethyldioctadecylammonium chloride, cetrimonium bromide, dioctadecyldimethylammonium bromide, tetradecyltrimethylammonium borine, benzalkonium chloride (BK), hexadecylpyridinium chloride monohydrate, and hexadecyltrimethylammonium bromide. A preferred material is benzalkonium chloride.

[0091] While not limiting, potentially useful nonionic surfactants include the following. Sodium polyoxyethylene glycol dodecyl ether, N-decanoyl-N-methylglucamine, digitonin, n-dodecyl β-D-maltoside, octyl β-D-glycopyranoside, octyl phenol ethoxylate, polyoxyethylene (8) iso-octyl phenyl ether, polyoxyethylene sorbitan monolaurate, and polyoxyethylene (20) sorbitan, chloramidopropyl dimethylammonio]-2-hydroxy-1-propane sulfonate, 3-[(3-chloramidopropyl) dimethylammonio]-1-propane sulfonate, 3-(decyl dimethylammonio) propane sulfonate inner salt, N-dodecyl-N,N-dimethyl-3-ammonio-1)-propane sulfonate.

[0092] While not limiting, potentially useful zwitterionic surfactants include the following. Sulfonates (e.g., 3-[(3-cholamide propyl) dimethylammonio]-1-propane sulfonate), sultaines (e.g., cocamidopropyl hydroxysultaine), betaines (e.g., cocamidopropyl betaine), and phosphates (e.g., lecithin).

[0093] For other potentially useful materials, the interested reader is referred to other substances shown in, for example, U.S. Patents 4,107,328 and 6,953,772, and U.S. Patent Publication No. 2007 / 0264310.

[0094] When a surfactant is included in the formulation, the amount can vary widely based on various factors including, but not limited to: the age of the biofilm (especially whether it is entrenched, a factor related to the type of protein and the amount of the macromolecular matrix), the size of the biofilm, the amount of surface fouling, the species of bacteria, whether two or more types of bacteria are present, and the solubility of the surfactant.

[0095] The amount of surfactant is generally at least about 0.02%, typically at least about 0.04%, typically at least about 0.06%, typically at least about 0.08%, and typically at least about 0.10% (all w / w based on the total weight of the composition). Some compositions can contain more surfactant, for example at least about 0.12%, at least about 0.13%, at least about 0.14%, at least about 0.15%, at least about 0.16%, at least about 0.2%, at least about 0.25%, at least about 0.5%, at least about 0.75% and at least 1% (all w / w based on the total weight of the composition). The maximum amount of surfactant added can be determined by the solubility limit of the particular surfactant chosen. (Any two of the previous minimum amounts can also be combined to provide a typical range of surfactant amounts.)

[0096] Sometimes, the maximum amount of certain types of surfactants that can be present in compositions for specific end - uses (without specific tests, investigations, and approvals) is set by government regulations. For example, in compositions intended to contact food without rinsing, the maximum is 0.02% (by weight) of BK; in compositions intended for oral rinsing applications, the maximum is 0.1% (by weight) of CPC (and an additional 0.13% (by weight) of BK can be present as a preservative); in compositions intended for use on damaged or undamaged skin, the maximum can include 0.13% (by weight) of BK. In compositions used for the purpose of sterilizing medical devices, various surfactants can be used in amounts of at least 1% (by weight), often up to about 2% (by weight) or more.

[0097] Antibacterial compositions can include various additives and adjuvants that are more useful for their use in specific end - uses, even if they essentially negatively affect their efficacy. Non - limiting examples include emollients, bactericides, perfumes, pigments, dyes, defoamers, foaming agents, flavors, abrasives, bleaching agents, preservatives, etc. (such as antioxidants). A comprehensive list of additives approved by the U.S. Food and Drug Administration is available at http: / / www.fda.gov / Drugs / InformationOnDrugs / ucmll3978.htm (a hyperlink to a compressed text file, valid as of the filing date of this application).

[0098] The composition does not require an active antibacterial agent for efficacy. However, such materials can be included in some embodiments. Non - limiting examples of potentially useful active antibacterial agent additives include C 2 -C 8Alcohol (other than or in addition to those used as the organic liquid of the solvent component), for example, ethanol, n-propanol, etc.; aldehyde, for example, glutaraldehyde, formaldehyde and o-phthalaldehyde; compounds that generate formaldehyde, for example, noksythiolin, taurine, hexamine, urea formaldehyde, imidazolone derivatives, etc.; anilide, especially triclocarban; biguanide, for example, chlorhexidine and alexidine, and polymers in the form of, for example, (poly(hexamethylene biguanide)); dicarboxyimidamide, for example, substituted or unsubstituted propamidine) and their isethionate salts; compounds containing halogen atoms or compounds that release halogen atoms, for example, bleaching agents, C1O 2 、dichloroisocyanurate, tosylchloramide, iodine (and iodophors), etc.; silver and silver compounds, for example, silver acetate, silver sulfadiazine and silver nitrate; peroxides, for example, H 2 O 2 and peracetic acid; phenol, bisphenol and halophenol ((including hexachlorophene) and phenoxyphenol (for example, triclosan)); and quaternary ammonium compounds. Furthermore, antibiotics may be added for medical use.

[0099] Based on the foregoing description, it can be seen that the non-solvent portion of the composition consists of, or consists essentially of, solutes (especially those derived from buffer precursors alone or in combination with other solutes) and ions resulting from the dissociation of acids or bases. In other embodiments, the non-solvent portion consists of, or consists essentially of, solutes, ions resulting from the dissociation of acids or bases, and one or more surfactants. In other embodiments, the non-solvent portion consists of, or consists essentially of, solutes, ions resulting from the dissociation of acids or bases, one or more surfactants, and a bleaching agent solution of less than 1% w / v.

[0100] Other forms may be desirable for certain end uses, but the composition can be provided as a solution product that can be used as is for convenience, or as a concentrate. Thus, the composition can be provided as a soluble powder (an option that can be diluted later and reduce shipping costs), a slurry or in a more concentrated form such as a gel or paste (which is particularly useful for providing an increased residence time).

[0101] The composition can be provided as a gel or coating, which elutes the active substance, disinfects the surface, and prevents surface colonization.

[0102] In the case of gels, the liquid form of the composition can be formulated on an oily, absorbent, water / oil emulsion, oil / water emulsion or water-miscible carrier base. Examples of oily bases include white petrolatum and the base of white ointment. Examples of absorbent bases include hydrophilic petrolatum, dehydrated lanolin, and those used in products such as Aquabase®, Aquaphor® and Polysorb® ointments. Water / oil bases include cold cream-type bases, lanolin, and those used in products such as Hydrocream®, Eucerin® and Nivea® moisturizers. Oil / aqueous bases include hydrophilic ointment, and those used in products such as Dermabase®, Velvachol® and Unibase® ointments. Water-miscible bases include PEG ointment, cellulose gels, chitosan gels, polyvinylpyrrolidone, and those used in products such as Polybase® ointments.

[0103] Examples of solvent-containing compositions that can be provided as a stable gel are shown in Table 3. ("Stable" means that there is no substantial loss of efficacy or change in appearance after several months of storage at room temperature.) Each had an effective pH of 4.0 and an osmolality of 2.33 Osm / L; the first two had 10% w / v co-solvent (DGME and IPA, respectively), and the third had 1% w / v co-solvent phenoxyethanol (the US Food and Drug Administration regulations allow much less quantity of this material in compositions intended for skin contact).

[0104]

Table 3

[0105] The coating can be formulated from the previous gel form or incorporated into more adhesive and stable products such as latex, silicone, polyurethane, cross-linked PEG, chitosan gel, or a coalescent such as polyvinylpyrrolidone.

[0106] Regardless of the physical form of the composition, increasing the temperature and / or agitation during application processing has a beneficial effect on the sterilization rate and overall sterilization. Since the composition dissolves and / or disrupts the macromolecular matrix and extracts bacterial cell wall proteins, it is preferred to apply the composition in a fluid-like manner. That is, the EPS macromolecules that are partially or fully solvated can be removed from the treatment area, which prevents it from blocking the treatment chemicals and allows fresh composition to be introduced to the bacterial cell wall.

[0107] The composition can be used in various ways. For example, when used to treat biofilms on surfaces (such as cutting boards, counters, desks, etc.), the composition can be applied directly to the biofilm. Optionally, subsequent physical rubbing or buffing can be done, or the composition can be applied to a friction / buffing medium (such as a cloth). When treating biofilms in hard-to-reach places, the excess composition can be soaked or immersed in the biofilm for a time sufficient to essentially solvate the biofilm, and then rinsed away from the affected area. Regardless of the contact method, the surfactant component is thought to kill a significant number of bacteria without the need for the bacteria to be removed from the biofilm or the biofilm to be removed from the bacteria. The solution can be applied by many means including spraying, or is allowed to flow over the surface. It can be applied under pressure or without pressure, can be applied with a wet wipe or dressing, or can be applied using ultrasound.

[0108] The composition according to the present invention is superior to equivalent compositions that do not contain an organic liquid in the solvent component in both the kill count and rate of bacteria (the time required to achieve an acceptable reduction in the amount of bacteria). This is true even when the amount of the surfactant component is significantly reduced or omitted. Thus, a composition containing a solvent component with a δp value of about 15.5 will reduce Pseudomonas aeruginosa by 1 - 3 logs and Staphylococcus aureus by 1 - 2 logs compared to an aqueous composition having a δp value of 16.0 under the same test conditions; a composition containing a solvent component with a δp value of about 15.0 (i.e., 14.9 - 15.2) will show superior efficacy, for example showing a large reduction of 3 to 6 logs for Pseudomonas aeruginosa and 2 to 3 logs for Staphylococcus aureus. A graph of the impact of the δp value of the solvent component on efficacy can be seen, for example, in Figure 6.

[0109] Depending on the abundance of microbial contamination, the compositions of the present invention have many potential uses, including but not limited to: residential, commercial, and industrial hard surfaces, such as bathroom surfaces (floors, countertops, sinks, drain pipes including floors and sinks, showers, toilets, toilet seats, walls, floors, buckets, shower curtains and shower doors, fixtures including shower fixtures); kitchen surfaces (countertops, floors, stove surfaces, sinks and water pipes, cutting boards, pots, pans, dishes, tableware, cooking and serving utensils, inner surfaces of dishwashers, all types of food processing equipment, coffee makers, ice makers, etc.); industrial food processing equipment surfaces, such as meat, poultry, seafood, dairy farms, production and beverage processing (floors, drain pipes, surfaces for cutting and preparation, packaging surfaces, processing equipment, sewage tanks, cabinets, surfaces of transfer belts for fluid lines and chambers, etc.), and food surfaces, animal carcasses, their cuts, egg washing, and product washing by immersion spraying or other means.

[0110] Furthermore, the compositions of the present invention can be used, including but not limited to, for example, health examination / healthcare surfaces, such as surgical supplies (e.g., tables, trays, floors, walls, sinks, drains, any instruments and tools, implant devices, devices before installation, or those handled inside the body during surgery); respirators; reprocessing of devices such as various types of scopes (e.g., endoscopes, gastric cameras, laparoscopes, etc.); dialysis machines; all types of analyzers for blood, urine, or other tissue / fluid samples; reprocessing of implant devices or surgical instruments, especially those that may cause problems when autoclaved due to heat sensitivity, and final sterilization before surgical use; patient care surfaces, such as floors, walls, sinks, fixtures, toilets, drain pipes, bed rails and frames, telephones, remote control devices for audiovisual equipment, tables, chairs, etc.; cleaning of contact lenses and preparation, cleaning, and / or sterilization of dentures.

[0111] Biofilms and biofouling reduce the energy efficiency of production processes by many mechanisms, including increased surface friction, degradation of metal components, blockage of fluid lines, coating of surfaces, and decreased heat transfer coefficients. The compositions of the present invention can counteract such detrimental effects in industrial applications. Uses include, for example, cleaning and / or preparing chemical reactors; processing and repackaging, particularly when maintenance requiring repeated contamination is required; treating surfaces with biofouling that causes corrosion or heat transfer characteristics harmful to function; production and pumping equipment, drilling equipment for oil and gas production (e.g., controlling biofouling that interferes with or reduces production); all cases where bacterial contamination results in problems with steam or chemical changes, such as bacterial growth in biodiesel and souring during gas storage.

[0112] Other surfaces that can benefit from the application of the compositions of the present invention include, regardless of form: toys, baby pacifiers, door handles, grocery carts, telephones, remote control devices, washing machine drums, humidifiers, dehumidifiers, air conditioning condensers, automobile piping, air handling piping, trash cans, reverse osmosis filter elements, and ion exchange filter elements.

[0113] Other potential uses for the compositions of the present invention include the following: fabrics and textiles, such as for the washing of general clothing, particularly for the removal of malodors, for hospital linens for sterilization or sanitization, for the cleaning of infant clothing for sterilization or sanitization, and for bandages; the treatment of living human or animal tissue, such as for the treatment of rhinitis (direct washing of the nasal cavity or with a packaging material), for the treatment of otitis, for surgical site preparation, for surgical washing, for the rinsing of a surgical site during or before surgery, particularly when provided directly in the surgical site as a gel - foam or when left to surround an implant or transplanted device such as a pacemaker, for providing extended antibacterial protection for something remaining in the body after closure, for the treatment of wounds, for a gel - like wash intended to remain on the wound for an extended period, or for use as a treatment solution in a negative pressure wound therapy device, for the treatment of cystic fibrosis to remove biofilms from the lungs, for the treatment of tonsils and adenoids, as an antibacterial hemostatic agent in combination with a suitable coagulating agent, for oral care as a rinse or toothpaste, for the rinsing of teeth filled after root canal treatment, for the treatment of endodontic fungi, yeast infections, diaper rash, acne, hand sanitizers, skin cleansers, udder rot, foot rot, for the treatment of metritis, dairy teat dip, etc.; flow - channel devices, such as in dental unit water lines, recirculating cooling / heating loops (open or closed systems) such as in cooling towers and heat exchangers, production equipment or laboratory instruments, recirculation loops for lubricants and cutting oils, processing equipment such as chemical reactors, fermentation tanks, liquid and beverage packaging, any system including sewage tanks, fluid transfer lines and valves, joints or dispensers for aqueous systems, condensate collection and transfer lines, particularly steam lines where steam is present, transport tanks such as for truck or rail transport.

[0114] Although various embodiments of the present invention have been provided, they are presented by way of example and not limitation. The following claims and their equivalents define the breadth and scope of the methods and compositions of the present invention. Also, the methods and compositions of the present invention are not limited by any of the preceding exemplary embodiments.

[0115] To aid in understanding the foregoing description, the following definitions are provided. These definitions are intended to apply as such unless the surrounding text explicitly indicates a contrary intention. "Comprising" means including the listed components, but not limited to them. "Consisting of" means including only the listed components and minor amounts of inert additives and adjuvants. "Consisting essentially of" means including only the listed components and minor amounts (less than 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25% or 0.1% w / v) of other components that either supplement antibacterial activity and / or provide desirable secondary effects (e.g., anti-clouding, soil removal, wound cleaning, etc.) for the intended end use, and / or inert additives and adjuvants. "Bacteria" means all types of microorganisms, including but not limited to, for example, bacteria, viruses, fungi, virus-like entities, prions, and the like. "Antibacterial agent" means a substance having the ability to reduce the number of one or more bacteria by more than 90% (1 log). "Active antibacterial agent" means an antibacterial agent that is effective only during or predominantly during the active phase of the life cycle, such as bacterial cell division. "Biofilm" means a community of bacteria, particularly a community of bacteria and fungi, whose members are attached to a surface and are either within or protected by a self-generated polymeric matrix. "Mature biofilm" is a biofilm that has reached a steady-state mass after a growth period of two or more days. "Buffer" means a compound or mixture of compounds having the ability to maintain the pH of an added solution within a relatively narrow range; "Buffer precursor" means a compound that reverts to a buffer when added to a mixture containing an acid or a base; "Polyacid" means a compound having at least two carboxyl groups, including dicarboxylic acids, tricarboxylic acids, etc.; "Benzalkonium chloride" refers to a compound defined by the following general formula.

[0116] [Chemical formula]

[0117] R 3 is C 8 -C 18 an alkyl group, or any mixture of such compounds; "Residence time" refers to the time during which contact between the antibiotic and the biofilm of bacteria is permitted; "Biocompatibility" means not showing significant long-term harmful effects in mammalian species; "Biodegradation" means the conversion of a chemical substance into smaller chemical species by an enzymatic process, chemical process or physical process in vivo; "Biosorption" means the absorption of a material into the body of a mammalian species; "Absorption base" is a blend of a fatty base and one or more surfactants; "Bleach solution" is an aqueous composition containing from about 4.0% to about 6.5% (by weight) of hypochlorite ions and having a pH of 10 ≦ pH ≦ 12; "Soil load" means a solution of one or more organic and / or inorganic substances added to a suspension of a test organism to simulate the presence of body secretions, feces, etc.; "Inoculum" means a solution containing bacteria, a growth solution (e.g., tryptic soy broth) and a protein soil load; "Replaced" means containing a heteroatom or functional group (e.g., a hydrocarbyl group) that does not interfere with the intended purpose of the base of the problem.

[0118] Examples In the following examples, many tests are conducted to evaluate various antibacterial compositions against bacteria in various formats. A brief description of these tests is as follows: Quantitative carrier test (QCT) (ASTM Test Method E2197-02 (§ 9)): Three separate vessels (each 10 mL KH 2 PO 4 solution (containing about 30% w / v in water)) were each added with 0.5 g of tryptone, 0.5 g of bovine serum albumin and 0.04 g of bovine mucin; each was sterilized separately. In separate containers, 340 microliters of a microbial suspension (bacteria grown from a suspension obtained from ATCC, Manassas, Virginia), 25 microliters of a BSA solution, 100 microliters of a mucin solution, and 35 microliters of a tryptone stock were added together to provide a soil-loaded bacterial suspension for use immediately after preparation. An aliquot of 10 microliters of the soil-loaded bacterial suspension was applied to a clean stainless steel disk, dried, and an aliquot of 50 microliters of the antibacterial composition was applied. The results of this test are reported as a decrease (logarithmic scale) from the control. Biofilm CDC reactor test (ASTM E2871)-12: Biofilms were grown on coupons in a CDC reactor (ASTM E-2562). Upon removal, the coupons were immersed in sterile water containing buffer to remove planktonic bacteria, placed in sterile 50 mL conical tubes, and 4 mL of the antimicrobial composition was added thereto. After the specified residence time (e.g., 3, 5, or 10 minutes), 36 mL of Day / Engler broth (commercially available from various sources, e.g., Sigma-Aldrich) was added to the tubes to stop further antibiosis of the composition and to quantify the remaining bacterial load. Results are reported as a decrease (log scale) from the control. Planktonic bacteria test (AOAC 955.14, 955.15, 964.02): Soil load (about 10 6 suspended bacteria) is applied to many penicillin cylinders (typically 60). It is placed in a sterile test tube containing 10 mL of the antimicrobial composition. After the treatment time (e.g., 3, 5, or 10 minutes), the cylinders are transferred to test tubes containing growth media, nutrients (e.g., Day / Engler broth), and a pH-sensitive dye that changes color when the pH drops below neutral (which occurs during cell respiration by any bacteria living in the penicillin cylinders after treatment). Results are provided as the amount of time (seconds) required to completely disinfect the test surface, and a visual color test is performed. (When 60 test cylinders are run, 58 must show no color change to achieve a passing result.)

[0119] Precursor buffer compositions A through M shown in Table 4 are prepared and 37% (by weight) HCl or 50% (by weight) NaOH is added to achieve the target pH.

[0120] Examples 1 - 24 Twenty-four antimicrobial compositions were prepared: Examples 1-8 contained 1.78 g (0.008 mol) of SDS anionic surfactant, Examples 9-16 contained 2.10 g (0.008 mol) of BK cationic surfactant, and Examples 17-24 contained no additional surfactant.

[0121] All of these compositions were prepared to have an effective solute concentration of 2.33 Osm / L, with half of the compositions from each of the three groups being acidic (pH=4.0) and the other half being alkaline (pH=10.0): the acidic (Examples 1-4, 9-12 and 17-20) used 127.0 g / L citric acid and 112.5 g / L sodium citrate dihydrate, and the alkaline (Examples 5-9, 13-16 and 21-24) used approximately 19.4 g / L NaOH and 65.0 g / L KH 2 PO 4 was used.

[0122] Each composition was prepared in a 100 mL glass container and prepared by adding surfactant (if used), buffer precursor (salt), and then acid or base to disperse it in enough water.

[0123] Each of the compositions of Examples 1-4 was mixed with the following organic liquid (the numbers shown are the MPa of the solvent component of the resulting composition): 1 / 2 10 g of one of the following compounds (δp values ​​at 1000 nm): PGME (14.96), DGME (15.32), IPA (15.01), or DMSO (16.04) was then added to each solution at 100 mL, and the vessels were covered and stored at room temperature (approximately 23 °C).

[0124] The previous solvent and water additions were repeated for the compositions in the other groups (i.e., Examples 5-8, 9-12, 13-16, 17-20, and 21-24).

[0125] The compositions are summarized in Table 4 below.

[0126] [Table 4]

[0127] To evaluate their effectiveness against planktonic bacteria, soil-inoculated bacteria, and bacteria in biofilm form, these compositions were evaluated in numerous experiments. The results of the tests of these compositions are summarized in Table 5 below. Here, "SA" represents Staphylococcus aureus, "PA" represents Pseudomonas aeruginosa, and "EC" represents Escherichia coli.

[0128]

Table 5

[0129] Even if sterilization was not achieved, the antibacterial efficacy of the compositions against Staphylococcus aureus in Table 4 was not tested for more than 60 seconds.

[0130] The decrease in bacteria versus the δp value of the solvent component of the composition was plotted, and the results were shown as follows: Figure la Staphylococcus aureus QCT data, pH = 4 composition Figure lb Staphylococcus aureus QCT data, pH = 10 composition Figure 2a Staphylococcus aureus CDC reactor (biofilm), pH = 4 composition Figure 2b Staphylococcus aureus CDC reactor (biofilm), pH = 10 composition Figure 3a Pseudomonas aeruginosa CDC reactor (biofilm), pH = 4 composition Figure 3b Pseudomonas aeruginosa CDC reactor (biofilm), pH = 10 composition

[0131] In each of these plots, when the δp value drops to about 15.2 MPa 1 / 2 or less, a clear increase in efficacy is seen. The exact point at which the discontinuity begins varies somewhat between the planktonic bacteria and biofilm tests, but the transition occurs at 15.2 ≤ δp ≤ 15.4 MPa 1 / 2 and occurs.

[0132] Furthermore, plots for Staphylococcus aureus at pH = 10 containing cationic surfactants (Figs. 1b and 2b) show efficacy beyond the theoretical boundary. Although not bound by theory, different (sub)sections of the proteins in the wall of this bacterium may become soluble at δp values corresponding to anomalous log reduction data points.

[0133] Data from Table 5 appear to show that the pH = 4 compositions are generally somewhat more effective than the pH = 10 compositions, and that compositions containing cationic surfactants are more effective than those containing anionic surfactants and their surfactant-free counterparts. However, the latter also demonstrated significant antibacterial capabilities.

[0134] After the previous tests were completed, the respective correlations of HSPs to the results were evaluated. Basic regression analysis was performed on the results of the individual parameters and the interaction radius value. The results of the fit and probability for this regression analysis are shown in Table 6 below.

[0135]

Table 6

[0136] The previous data show that for Staphylococcus aureus and Pseudomonas aeruginosa, the δp parameter has the best fit and the lowest p-value. For the solutions evaluated, the δd and δp parameters show the same trend in solution. Therefore, when regression is performed against efficacy, there will be a strong correlation between these parameters. Thus, δd values are expected to be useful in formulating the compositions. Also, in that case, the point of delimitation for solution efficacy will be functionally equivalent to the compositions derived from the δp values.

[0137] Examples 25 - 32 The preparation procedures of the compositions of Examples 1-24 were repeated except for the following differences (2.1 g / L of BK was used as surfactant in all): Examples 25-26 - 19.0 g / L NaOH, 66.0 g / L of KH 2 PO 4 (pH = 7.5 and 2.33 Osm / L), Examples 27-28 - 9.7 g / L NaOH, 32.5 g / L of KH 2 PO 4 (pH = 10.0 and 1.165 Osm / L), Examples 29-30 - 63.5 g / L citric acid, 56.3 g / L of sodium citrate dihydrate (pH = 4.0 and 1.165 Osm / L), Examples 31-32 - 19.4 g / L NaOH, 65.0 g / L of KH 2 PO 4 (pH = 10.0 and 2.33 Osm / L).

[0138] The amount of the organic liquid was varied to obtain the compositions shown in Table 7. Thereafter, it was subjected to a biofilm CDC reactor test. (All the compositions had a sterilization time of 15 seconds in the test of planktonic organisms.)

[0139]

Table 7

[0140] The pH = 10 and 2.33 Osm / L compositions from Examples 1-24 and 25-32 were identified and their log reduction vs. δp value data were plotted. They were plotted together with the Staphylococcus aureus results in Figure 4 and the Pseudomonas aeruginosa results in Figure 5. They show a significant increase in antibacterial power near a δp value of about 15.3 MPa 1 / 2 .

[0141] Examples 33-43 To remove test-to-test variations and to eliminate the potentially confounding effects of using different solvents, the biofilm tests used in Examples 1-24 were conducted by varying the concentration of one solvent (PGME) from 0 to 10% w / v and varying the exposure time.

[0142] PGME was added to a composition containing 2.1 g / L of BK, 19.4 g / L of NaOH and 65.0 g / L of KH 2 PO 4 (pH = 10.0 and 2.33 Osm / L).

[0143] The bacterial reduction data from these tests plotted against the δp values are shown in Figure 6. It shows that the efficacy of the composition increases dramatically with decreasing δp values of the solvent component and with increasing application time. (10-minute application at δp = 15.38 and δp = 15.17 MPa 1 / 2 and 5-minute application at δp = 15.17 MPa 1 / 2 give complete sterilization of the biofilm.) Compositions containing no additional PGME were not tested for 3-minute application. Examples 44 - 64

[0144] To evaluate the efficacy of the antimicrobial composition for medical use, the test was attempted using a mixed-species biofilm wound model in a drip flow reactor. Mixed-species biofilms are usually more difficult to disinfect and result in a wider spread of data.

[0145] A mixed-species biofilm of Pseudomonas aeruginosa and Staphylococcus aureus was grown on microscope slides coated with hydroxyapatite in a drip flow reactor at low flow rate (10 mL / hour) to obtain a biofilm of 10 7 to 10 8 CFU / cm.

[0146] Thereafter, the test composition was applied to all but one slide for 5 minutes without flow. After the slide was harvested, the log reduction value was obtained by determining the amount of bacteria on the control slide and the test sample and subtracting the latter from the former.

[0147] The compositions tested were prepared as in Examples 1-24. The specific amounts of the various components were as follows: Examples 44-49 - 2.1 g / L of BK, 21.7 g / L of NaOH, 74.7 g / L of KH 2 PO 4 (pH = 9.0 and 2.33 Osm / L), Examples 50-52 - 2.1 g / L of BK, 22.0 g / L of NaOH, 73.7 g / L of KH 2 PO 4 (pH = 10.0 and 2.33 Osm / L), Examples 53-54 - 1.3 g / L of BK, 48.0 g / L of citric acid, 42.5 g / L of sodium citrate dihydrate (pH = 4.0 and 880 mOsm / L), Examples 55-56 - 1.3 g / L of BK, 0.5 g / L of Na 2 CO 3 , 37.5 g / L of NaHCO 3 (pH = 8.0 and 880 mOsm / L), Examples 57-59 - 1.3 g / L of BK, 1.0 g / L of Na 2 CO 3 , 75.0 g / L of NaHCO 3 (pH = 8.0 and 1.76 Osm / L), Examples 60-62 - 1.3 g / L of BK, 8.2 g / L of NaOH, 28.2 g / L of KH 2 PO 4 (pH = 9.0 and 880 mOsm / L), Examples 63-64 - 1.3 g / L of BK, 16.4 g / L of NaOH, 56.4 g / L of KH 2 PO 4 (pH = 9.0 and 1.76 Osm / L).

[0148] The performance of these compositions in the CDC biofilm test is shown in Table 8 below.

[0149]

Table 8

[0150] For all buffer systems and pH values, and for all bacteria, some variation was shown by the buffer system and specific bacteria, but the compositions with lower δp values showed higher efficacy against similar compositions with higher δp values. However, generally, as the δp value decreased from about 15.5 to about 15.1 MPa 1 / 2 a substantial increase in efficacy was seen.

[0151] Examples 65 - 80 Further tests were conducted to consider the relative importance of pH and permeability, and the relative effect of the organic liquids that regulate the δp value.

[0152] The compositions tested were prepared as in Examples 1 - 24. The specific amounts of the various components were as follows: Examples 65 - 66 - 19.0 g / L of NaOH, 66.0 g / L of KH 2 PO 4 (pH = 7.5 and 2.33 Osm / L), Examples 67 - 68 - 9.7 g / L of NaOH, 32.5 g / L of KH 2 PO 4 (pH = 10.0 and 1.165 Osm / L), Examples 69 - 70 - 63.5 g / L of citric acid, 56.3 g / L of sodium citrate dihydrate (pH = 4.0 and 1.165 Osm / L), Examples 71 - 76, 79 - 19.4 g / L of NaOH, 65.0 g / L of KH 2 PO 4 (pH = 10.0 and 2.33 Osm / L), Example 77 - 127.0 g / L of citric acid, 112.5 g / L of sodium citrate dihydrate (pH = 4.0 and 2.33 Osm / L), Example 78, 80 - 9.5 g / L of NaOH, 33.0 g / L of KH 2 PO 4 (pH = 7.5 and 1.165 Osm / L).

[0153] Each of Examples 65 - 77 further contained 2.1 g / L of BK, and Examples 78 - 80 did not contain additional surfactants.

[0154] In these examples, one of the following solvents was added: PGME, IPA, ethyl acetate (EA, δp = 5.3) or chlorobenzene (CB, δp = 4.3). The specific solvent added, the amount added, and the effectiveness of the resulting composition against biofilms in the CDC reactor tests are summarized in Table 9 below.

[0155]

Table 9

[0156] The reduction of bacteria versus the δp values of the solvent components of the compositions from Examples 9 - 12 and 71 - 76 are plotted, and the results are shown below. Figure 7 - Staphylococcus aureus CDC reactor (biofilm), (composition at pH = 10) Figure 8 - Pseudomonas aeruginosa CDC reactor (biofilm), (composition at pH = 10).

[0157] Figures 7 - 8 visually show that with the decrease in δp value, the efficacy against both Staphylococcus aureus and Pseudomonas aeruginosa increases. The effect against the latter is greater.

[0158] The pH of the compositions of Example 9, 11, 13 and 15, and Examples 65 - 66 (all of which had 10% (w / v) solvent, 2.1 g / L cationic surfactant added and were at 2.33 Osm / L) against the reduction of bacteria was plotted, and the results are shown in Figure 9 (Staphylococcus aureus) and Figure 10 (Pseudomonas aeruginosa). These plots seem to show that compositions with more neutral values are significantly effective against Pseudomonas aeruginosa, while acidic compositions (lower pH values) have greater efficacy against Staphylococcus aureus than higher pH solutions. Based on this, the osmotic pressure of the composition seems to have a stronger impact on efficacy than pH. This suggests that a moderately gentle composition on the surface can be very effective against the target bacteria.

[0159] The effective solute concentrations of the compositions from the reduction of bacteria of Example 9, 11, 13, 15, 60, 67 - 68 and 70 (all of which contained 2.1 g / L cationic surfactant and 10% w / v organic liquid) were plotted, and the results are shown in Figure 11 (Staphylococcus aureus) and Figure 12 (Pseudomonas aeruginosa). In Figure 11, the low pH compositions seem to tend to show increased efficacy with an increase in effective solute concentration. However, the high pH compositions do not seem to follow this trend. In Figure 12, the compositions containing DGME show the expected trend of increased efficacy with an increase in effective solute concentration, while the compositions containing IPA do not show this trend.

[0160] Examples 81 - 88 Additional tests of planktonic organisms (AOAC) were conducted to determine the results when changing the δp value of the solvent component on the efficacy of the composition against soil - loaded Staphylococcus aureus bacteria. The compositions each used KH 2 PO 4 as buffer and IPA as solvent. The osmotic pressure of each composition was 2.33 Osm / L.

[0161] Thirty parts of each composition were each for 300 seconds (about 10 6Tested with a soil - loaded bacterial sample of CFU / carrier. Any visual indication of growth (i.e., color change from yellow to purple) was scored as a failure.

[0162] The percentage of passing the test is shown in the following table along with the pH, the amount of surfactant, and the δp value of the solvent component.

[0163]

Table 10

[0164] The data in Table 10 are plotted in Figures 13 (efficacy of the composition as a function of the δp value of the solvent component) and 14 (efficacy of the composition as a function of the concentration of the surfactant).

[0165] Figure 13 clearly shows a correlation between efficacy and decreasing δp values. The graph also appears to show that higher pH compositions retain efficacy even at higher δp values, but that the pH has little effect once the δp value passes a certain inflection point.

[0166] Figure 14 shows that changes in surfactant concentration have little effect. However, increasing the amount of IPA has a very large impact on efficacy due to a decrease associated with a decrease in the δp value of the solvent component.

Claims

1. 1. An antimicrobial cleanser for skin comprising a solution having an effective solute concentration of at least 2.0 Osm / L and a pH value of 3.5 to 5.5, a) the solvent component of the solution comprises water and at least one glycol; b) an antimicrobial cleaning agent, the solute components of said solution comprising at least 1% by weight of one or more of anionic surfactants, dissociation products of polyacids, and dissociation products of salts of polyacids.

2. 10. The antimicrobial cleaner of claim 1, wherein the solution has an effective solute concentration of at least 2.5 Osm / L.

3. 10. The antimicrobial cleaner of claim 1, wherein the solution has an effective solute concentration of at least 3 Osm / L.

4. 4. The antibacterial cleaner of claim 1, wherein the solute component further comprises at least 1% by weight of a zwitterionic surfactant.

5. 5. The antibacterial cleaner of claim 4, wherein the zwitterionic surfactant is cocamidopropyl betaine.

6. 6. The antibacterial cleanser of claim 1, wherein the at least one glycol in the solvent comprises glycerin.

7. 7. The antibacterial cleaner of claim 1, wherein the solute component comprises at least two anionic surfactants, each in an amount of at least 1% by weight.

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