Classifications

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  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
  • A61K31/231—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having one or two double bonds
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  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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  • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
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• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Definitions

• antimicrobial agents plays an important part in current medical therapy. This is particularly true in the fields of dermatology as well as skin and wound antisepsis, where the most effective course of treatment for skin or mucous membranes (e.g., as in the nasal cavities and in particular the anterior nares), which are afflicted with bacterial, fungal, or viral infections or lesions, frequently includes the use of a topical antimicrobial agent. For decades medicine has relied primarily upon antibiotics to fight systemic as well as topical infections.
• bacitracin for example, bacitracin, neomycin sulfate, polymyxin B sulfate, gentamicin, framycetin-gramicidin, lysostaphin, methicillin, rifampin, tobramycin, nystatin, mupirocin, and combinations thereof, as well as many others, have been used with varying success.
• Antibiotics are generally effective at very low levels and are often safe with very few, if any, side effects. Often antibiotics have little or no toxicity to mammalian cells. Thus, they may not retard, and can even enhance, wound healing. Antibiotics are generally of a narrow spectrum of antimicrobial activity. Furthermore, they often act on very specific sites in cell membranes or on very specific metabolic pathways. This can tend to make it relatively easy for bacteria to develop resistance to the antibiotic(s) (i.e., the genetically acquired ability to tolerate much higher concentrations of antibiotic) either through natural selection, transmission of plasmids encoding resistance, mutation, or by other means.
• Antiseptics tend to have broader spectrum of antimicrobial activity and often act by nonspecific means such as disruption of cell membranes, oxidation of cellular components, denaturation of proteins, etc. This nonspecific activity makes it difficult for resistance to develop to antiseptics. For example, there are almost no reports of true resistance to antiseptics such as iodine, lower alcohols (ethanol, propanol, etc.), chlorhexidine, quaternary amine surfactants, chlorinated phenols, and the like. These compounds, however, need to be used at concentrations that often result in irritation or tissue damage, especially if applied repeatedly. Furthermore, unlike antibiotics, many antiseptics are not active in the presence of high levels of organic compounds. For example, formulations containing iodine or quaternary ammonium compounds have been reported to be inactivated by the presence of organic matter such as that in nasal or vaginal secretions, and perhaps even on skin.
• compositions for certain applications, especially in the nose and mouth, it is particularly desirable for the compositions to have little or no color, little or no odor, and an acceptable taste. This is not the case for many antiseptics such as iodine and iodophors, which have an orange to brown color and a definite odor.
• Some conventional antimicrobial compositions have used various carboxylic acids or fatty acids for the suppression of fungi, bacteria, molds, and the like. These compositions vary widely in their efficacy, stability, and levels of persistence. Plus, they possess an even wider variety of side effects. For example, many of these materials are viewed as irritants, particularly the C8-C12 fatty acids. This is particularly true for sensitive mucosal tissues, such as the anterior nares and nasal cavities, which can have a generally high level of microbial colonization in certain otherwise healthy individuals, as well as individuals with infectious diseases such as chronic siniusitis. Additionally, due to the irritating nature many of these agents would be unsuitable for application to irritated or infected dermal tissue such as lesions from impetigo and shingles or sensitive tissues such as the nasal cavities and especially the anterior nares.
• many conventional antimicrobial compositions are too low in viscosity and/or too hydrophilic in nature to maintain sufficient substantivity and persistence to provide sufficient antimicrobial activity on moist tissue, such as the anterior nares or open, exuding, or infected lesions, and the like.
• the present invention provides antimicrobial compositions and methods of using and making the compositions.
• Such compositions are typically useful when applied topically, particularly to mucosal tissues (i.e., mucous membranes), although a wide variety of surfaces can be treated. They can provide effective reduction, prevention, or elimination of microbes, particularly bacteria, fungi, and viruses.
• the microbes are of a relatively wide variety such that the compositions of the present invention have a broad spectrum of activity.
• compositions of the present invention provide effective topical antimicrobial activity and are accordingly useful in the local treatment and/or prevention of conditions that are caused, or aggravated by, microorganisms (including viruses, bacteria, fungi, mycoplasma, and protozoa) on skin and/or mucous membranes.
• microorganisms including viruses, bacteria, fungi, mycoplasma, and protozoa
• compositions of the present invention have a very low potential for generating microbial resistance.
• such compositions can be applied multiple times over one or more days to treat topical infections or to eradicate unwanted bacteria (such as nasal colonization of Staphylococcus aureus ).
• compositions of the present invention can be used for multiple treatment regimens on the same patient without the fear of generating antimicrobial resistance. This can be particularly important for chronically ill patients who are in need of decolonization of the anterior nares before hemodialysis, for example, or for antiseptic treatment of chronic wounds such as diabetic foot ulcers.
• compositions of the present invention have a generally low irritation level for skin, skin lesions, and mucosal membranes (including the anterior nares, nasal cavities, and nasopharangyl cavity). Also, certain preferred compositions of the present invention are substantive for relatively long periods of time to ensure adequate efficacy.
• compositions of the present invention include an antimicrobial lipid component that includes a fatty acid ester of a polyhydric alcohol, a fatty ether of a polyhydric alcohol, alkoxylated derivatives thereof (of either the ester or ether), or combinations thereof. Certain compositions further include an enhancer component. Other components that can be included as well are surfactants, hydrophilic components, and hydrophobic components. Compositions with hydrophobic components are typically used on skin, mucosal tissue, wounds, and medical devices that come in contact with such surfaces, whereas compositions with hydrophilic components are typically used on these surfaces as well as other hard surfaces (e.g., floor tiles).
• the present invention provides an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters include monoesters, diesters, or combinations thereof, and the ethers include monoethers, diethers, or combinations thereof; an effective amount of an enhancer component that includes an al
• the present invention provides an antimicrobial composition that includes: 0.01 wt-% to 20 wt-% of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters include monoesters, diesters, or combinations thereof, and the ethers include monoethers, diethers, or combinations thereof; 0.
• the present invention provides an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters include monoesters, diesters, or combinations thereof, and the ethers include monoethers, diethers, or combinations thereof; an effective amount of an enhancer component that includes an al
• the present invention provides an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters include monoesters, diesters, or combinations thereof, and the ethers include monoethers, diethers, or combinations thereof; an effective amount of an enhancer component that includes an al
• the present invention provides an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the ethers include monoethers, and for sucrose the ethers include monoethers, diethers, or combinations thereof; an effective amount of an enhancer component that includes an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C
• the present invention provides an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, and combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the ethers include monoethers, and for sucrose the ethers include monoethers, diethers, or combinations thereof; an effective amount of an enhancer component that includes an alpha-hydroxy acid, a beta-hydroxy acid, a chelating agent, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C
• the antimicrobial lipid component is present in an amount of at least 0.1 wt-%. Unless otherwise specified, all weight percents are based on the total weight of a “ready to use” or “as used” composition.
• the antimicrobial lipid component includes a monoester of a polyhydric alcohol, a monoether of a polyhydric alcohol, or an alkoxylated derivative thereof, then there is no more than 50 wt-%, more preferably no more than 40 wt-%, even more preferably no more than 25 wt-%, and even more preferably no more than 15 wt-% of a diester, diether, triester, triether, or alkoxylated derivative thereof present, based on the total weight of the antimicrobial lipid component.
• the antimicrobial lipid component includes glycerol monolaurate, glycerol monocaprate, glycerol monocaprylate, propylene glycol monolaurate, propylene glycol monocaprate, propylene glycol monocaprylate, and combinations thereof.
• the surfactant includes a sulfonate, a sulfate, a phosphonate, a phosphate, a poloxamer, a cationic surfactant, or mixtures thereof.
• the hydrophilic component includes a glycol, a lower alcohol ether, a short chain ester, and combinations thereof, wherein the hydrophilic component is soluble in water in an amount of at least 20 wt-% at 23° C.
• the present invention also provides various methods of use of compositions of the present invention.
• the present invention provides a method of preventing and/or treating an affliction caused, or aggravated by, a microorganism on skin and/or a mucous membrane.
• the method includes contacting the skin and/or mucous membrane with an antimicrobial composition of the present invention.
• the present invention provides a method of decolonizing at least a portion of the nasal cavities, anterior nares, and/or nasopharynx of a subject of microorganisms.
• the method includes contacting the nasal cavities, anterior nares, and/or nasopharynx with an antimicrobial composition of the present invention in an amount effective to kill one or more microorganisms.
• the present invention provides a method of decolonizing at least a portion of the nasal cavities, anterior nares, and/or nasopharynx of a subject of microorganisms.
• the method includes contacting the nasal cavities, anterior nares, and/or nasopharynx with an antimicrobial composition in an amount effective to kill one or more microorganisms, wherein the antimicrobial composition includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxid
• the present invention provides a method of treating a middle ear infection in a subject.
• the method includes contacting the middle ear, Eustachian tube, and/or tympanic membrane with an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters
• An alternative composition for treating a middle ear infection includes an effective amount of an antimicrobial lipid component, optionally an effective amount of an enhancer component, and a hydrophobic component which forms the greatest portion of the composition by weight (i.e., the hydrophobic component forms a vehicle for the active agent(s)).
• the present invention provides a method of treating chronic sinusitis in a subject.
• the method includes contacting at least a portion of the respiratory system (particularly the upper respiratory system including the nasal cavities, anterior nares, and/or nasopharynx) with an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the
• the present invention provides a method of treating impetigo on the skin of a subject.
• the method includes contacting the affected area with an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose the esters include monoesters, diesters, or combinations thereof, and the ether
• the present invention provides a method of treating and/or preventing an infection on the skin, mucosal tissue, and/or wound of a subject.
• the method includes contacting the skin, mucosal tissue, and/or wound with an antimicrobial composition in an amount effective to kill or inactivate one or more microorganisms, wherein the antimicrobial composition includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydr
• An alternative composition for treating and/or preventing an infection on the skin, mucosal tissue, and/or wound of a subject includes an effective amount of an antimicrobial lipid component, optionally an effective amount of an enhancer component, and a hydrophobic component which forms the greatest portion of the composition by weight.
• the present invention provides a method of treating a burn.
• the method includes contacting the burned area of a subject with an antimicrobial composition in an amount effective to kill or inactivate one or more microorganisms, wherein the antimicrobial composition includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for sucrose
• the present invention provides methods for killing or inactivating microorganisms.
• to “kill or inactivate” means to render the microorganism ineffective by killing them (e.g., bacteria and fungi) or otherwise rendering them inactive (e.g., viruses).
• the present invention provides methods for killing bacteria such as Staphylococcus spp., Streptococcus spp., Escherichia spp., Enterococcus spp., and Pseudamonas spp.
• Staphylococcus aureus including antibiotic resistant strains such as methicillin resistant Staphylococcus aureus ), Staphylococcus epidermidis, Escherichia coli ( E. coli ), Pseudomonas aeruginosa ( Pseudomonas ae .), and Streptococcus pyogenes , which often are on or in the skin or mucosal tissue of a subject.
• the method includes contacting the microorganism with an antimicrobial composition of the present invention in an amount effective to kill one or more microorganisms (e.g., bacteria and fungi) or inactivate one or more microorganisms (e.g., viruses, particularly herpes virus).
• microorganisms e.g., bacteria and fungi
• microorganisms e.g., viruses, particularly herpes virus
• the present invention provides a method of killing or inactivating microorganisms on the skin, mucosal tissue, and/or in a wound of a subject.
• the method includes contacting the affected area with an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ethers include monoethers, and for
• An alternative composition for killing or inactivating microorganisms on the skin, mucosal tissue, and/or in a wound of a subject includes an effective amount of an antimicrobial lipid component, optionally, an effective amount of an enhancer component, and a hydrophobic component which forms the greatest portion of the composition by weight.
• compositions of the present invention can also be used for providing residual antimicrobial efficacy on a surface that results from leaving a residue or imparting a condition to the surface (e.g., skin, mucosal tissue, wound, or medical device that comes in contact with such tissues, but particularly skin, mucosal tissue, and/or wound) that remains effective and provides significant antimicrobial activity.
• a condition e.g., skin, mucosal tissue, wound, or medical device that comes in contact with such tissues, but particularly skin, mucosal tissue, and/or wound
• the present invention provides a method of providing residual antimicrobial efficacy on the skin, mucosal tissue, and/or in a wound of a subject, the method includes contacting the skin, mucosal tissue, and/or wound with an antimicrobial composition that includes: an effective amount of an antimicrobial lipid component that includes a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, or combinations thereof, wherein the alkoxylated derivative has less than 5 moles of alkoxide per mole of polyhydric alcohol; with the proviso that for polyhydric alcohols other than sucrose, the esters include monoesters and the ether
• the present invention provides methods of preventing and/or treating a subject for a common cold and/or respiratory affliction caused by a microbial infection.
• the method includes contacting the subject with a composition of the present invention in at least a portion of the subject's respiratory system (such as but not limited to, at least a portion of the nasal cavities, etc.) in an amount effective to kill or inactivate one or more microorganisms that cause a common cold and/or respiratory affliction.
• An exemplary antimicrobial composition for use in this method includes an effective amount of an antimicrobial lipid component and an effective amount of an enhancer component.
• Effective amount means the amount of the antimicrobial lipid component and/or the enhancer component when in a composition, as a whole, provides an antimicrobial (including, for example, antiviral, antibacterial, or antifungal) activity that reduces, prevents, or eliminates one or more species of microbes such that an acceptable level of the microbe results. Typically, this is a level low enough not to cause clinical symptoms, and is desirably a non-detectable level.
• the concentrations or amounts of the components when considered separately, may not kill to an acceptable level, or may not kill as broad a spectrum of undesired microorganisms, or may not kill as fast; however, when used together such components provide an enhanced (preferably synergistic) antimicrobial activity (as compared to the same components used alone under the same conditions).
• the listed concentrations of the components are for “ready to use” or “as used” compositions.
• the compositions can be in a concentrated form. That is, certain embodiments of the compositions can be in the form of concentrates that would be diluted by the user with an appropriate vehicle.
• Hydrophilic or “water-soluble” refers to a material that will dissolve in water (or other aqueous solution as specified) at a temperature of 23° C. in an amount of at least 7% by weight, preferably at least 10% by weight, more preferably at least 20% by weight, even more preferably at least 25% by weight, and most preferably at least 40% by weight, based on the total weight of the hydrophilic material and the water.
• “Hydrophobic” or “water-insoluble” refers to a material that will not significantly dissolve in water at 23° C. No significant amount means less than 5% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and even more preferably less than 0.1% by weight, based on the total weight of the hydrophobic material and the water.
• “Stable” means physically stable or chemically stable, which are both defined in greater detail below.
• Enhancer means a component that enhances the effectiveness of the antimicrobial lipid component such that when the composition less the antimicrobial lipid component and the composition less the enhancer component are used separately, they do not provide the same level of antimicrobial activity as the composition as a whole.
• an enhancer component in the absence of the antimicrobial lipid component may not provide any appreciable antimicrobial activity.
• the enhancing effect can be with respect to the level of kill, the speed of kill, and/or the spectrum of microorganisms killed, and may not be seen for all microorganisms. In fact, an enhanced level of kill is most often seen in Gram negative bacteria such as Escherichia coli .
• An enhancer may be a synergist such that when combined with the remainder of the composition, the composition as a whole displays an activity that is greater than the sum of the activity of the composition less the enhancer component and the composition less the antimicrobial lipid component.
• Microorganism or “microbe” or “microorganism” refers to bacteria, yeast, mold, fungi, protozoa, mycoplasma, as well as viruses (including lipid enveloped RNA and DNA viruses).
• Antibiotic means an organic chemical produced by microorganisms that has the ability in dilute concentrations to destroy or inhibit microorganisms and is used to treat infectious disease.
• Antiseptic means a chemical agent that kills pathogenic and non-pathogenic microorganisms.
• Mucos membranes are used interchangeably and refer to the surfaces of the nasal (including anterior nares, nasoparangyl cavity, etc.), oral (e.g., mouth), outer ear, middle ear, vaginal cavities, and other similar tissues. Examples include mucosal membranes such as buccal, gingival, nasal, ocular, tracheal, bronchial, gastrointestinal, rectal, urethral, ureteral, vaginal, cervical, and uterine mucosal membranes.
• “Affliction” means a condition to a body resulting from sickness, disease, injury, bacterial colonization, etc.
• Treat” or “treatment” means to improve the condition of a subject relative to the affliction, typically in terms of clinical symptoms of the condition.
• Decolonization refers to a reduction in the number of microorganisms (e.g., bacteria and fungi) present in or on tissue that do not necessarily cause immediate clinical symptoms. Examples of decolonization include, but are not limited to, decolonization of the nasal cavity and wounds. Ordinarily fewer microorganisms are present in colonized tissue than in infected tissue.
• microorganisms e.g., bacteria and fungi
• Subject and “patient” includes humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, or other mammal.
• Wound refers to an injury to a subject which involves a break in the normal skin barrier exposing tissue below, which is caused by, for example, lacerations, surgery, burns, damage to underlying tissue such as pressure sores, poor circulation, and the like. Wounds are understood to include both acute and chronic wounds.
• a,” “an,” “the,” “at least one,” and “one or more” are used interchangeably.
• the term “and/or” means one or all of the listed elements (e.g., preventing and/or treating an affliction means preventing, treating, or both treating and preventing further afflications).
• the present invention provides antimicrobial (including, e.g., antiviral, antibacterial, and antifungal) compositions.
• These compositions include one or more antimicrobial lipids such as a fatty acid ester of a polyhydric alcohol, a fatty ether of a polyhydric alcohol, or alkoxylated derivatives thereof (of either the ester or ether).
• the compositions also include one or more enhancers.
• Certain compositions also include one or more surfactants, one or more hydrophilic compounds, and/or one or more hydrophobic compounds.
• compositions adhere well to bodily tissues (e.g., skin, mucosal tissue, and wounds) and thus are very effective topically.
• bodily tissues e.g., skin, mucosal tissue, and wounds
• the present invention provides a wide variety of uses of the compositions.
• Particularly preferred methods involve topical application, particularly to mucosal tissues (i.e., mucous membranes including the anterior nares and other tissues of the upper respiratory tract), as well as skin (e.g., skin lesions) and wounds.
• compositions containing an antimicrobial lipid component can be used, whereas in other applications in which more broad antimicrobial activity is desired, compositions containing both an antimicrobial lipid component and an enhancer component are used.
• compositions containing both an antimicrobial lipid component and an enhancer component are used.
• compositions of the present invention that contain an antimicrobial lipid component without an enhancer component may be suitable.
• compositions of the present invention can be used to provide effective topical antimicrobial activity.
• they can be used for hand disinfection, particularly in presurgical scrubs.
• They can be used to disinfect various body parts, particularly in patient presurgical skin antiseptics.
• compositions of the present invention can be used to provide effective topical antimicrobial activity and thereby treat and/or prevent a wide variety of afflications.
• they can be used in the treatment and/or prevention of afflictions that are caused, or aggravated by, microorganisms (e.g., Gram positive bacteria, Gram negative bacteria, fungi, protozoa, mycoplasma, yeast, viruses, and even lipid-enveloped viruses) on skin and/or mucous membranes, such as those in the nose (anterial nares, nasopharangyl cavity, nasal cavities, etc.), outer ear, and middle ear, mouth, rectum, vagina, or other similar tissue.
• microorganisms e.g., Gram positive bacteria, Gram negative bacteria, fungi, protozoa, mycoplasma, yeast, viruses, and even lipid-enveloped viruses
• mucous membranes such as those in the nose (anterial nares, nasopharang
• Particularly relevant organisms that cause or aggravate such afflications include Staphylococcus spp., Streptococcus spp., Pseudomonas spp., Enterococcus spp., and Esherichia spp., bacteria, as well as herpes virus, Aspergillus spp., Fusarium spp., and Candida spp.
• Particularly virulent organisms include Staphylococcus aureus (including resistant strains such as Methicillin Resistant Staphylococcus Aureus (MRSA), Staphylococcus epidermidis, Streptococcus pneumoniae, Enterococcus faecalis , Vancomycin Resistant Enterococcus (VRE), Pseudomonas auerginosa, Escherichia coli, Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Fusarium solani, Fusarium oxysporum, Fusarium chlamydosporum, Candida albicans, Candida glabrata , and Candida krusei.
• MRSA Methicillin Resistant Staphylococcus Aureus
• VRE Vancomycin Resistant Enterococcus
• Pseudomonas auerginosa Escherichia coli
• compositions of the present invention can be used for the prevention and/or treatment of one or more microorganism-caused infections or other afflictions.
• compositions of the present invention can be used for preventing and/or treating one or more of the following: skin lesions, conditions of the skin such as impetigo, eczema, diaper rash in infants as well as incontinent adults, inflammation around ostomy devices, shingles, and bacterial infections in open wounds (e.g., cuts, scrapes, burns, lacerations, chronic wounds); necrotizing faciitis; infections of the outer ear; acute or chronic otitis media (middle ear infection) caused by bacterial, viral, or fungal contamination; fungal and bacterial infections of the vagina or rectum; vaginal yeast infections; bacterial rhinitis; ocular infections; cold sores; genital herpes; colonization by Staphylococcus aureus in the anterior nares (e.g.
• compositions of the present invention can be used for preventing and/or treating a wide variety of topical afflictions caused by microbial infection (e.g., yeast, viral, bacterial infections).
• microbial infection e.g., yeast, viral, bacterial infections.
• compositions of the present invention can be used on a wide variety of surfaces.
• they can be used on skin, mucosal tissue, wounds, and hard surfaces such as medical (e.g., surgical) devices, floor tiles, countertops, tubs, dishes, as well as on gloves (e.g., surgical gloves). They can also be impregnated into cloth, sponges, and paper products (e.g., paper towels and wipes), for example.
• compositions with hydrophobic components are used on skin, mucosal tissue, wounds, and medical devices that come in contact with such surfaces, whereas compositions with hydrophilic components are used on these surfaces as well as other hard surfaces (e.g., floor tiles).
• compositions of the present invention also provides various methods of use of compositions of the present invention.
• Various embodiments of the present invention include: a method of preventing an affliction caused, or aggravated by, a microorganism on skin and/or a mucous membrane; a method of decolonizing at least a portion of the nasal cavities, anterior nares, and/or nasopharynx of a subject of microorganisms; a method of treating a middle ear infection in a subject (through the middle ear, the Eustachian tube, and/or the tympanic membrane); a method of treating chronic sinusitis in a subject (by treating at least a portion of the respiratory system, particularly the upper respiratory system, including the nasal cavities, anterior nares, and/or nasopharynx); a method of treating impetigo on the skin of a subject; a method of treating and/or preventing an infection on the skin, mucosal tissue, and/or wound
• compositions of the present invention can be used in situations in which there are no clinical indications of an affliction.
• compositions of the present invention can be used in methods of decolonizing at least a portion of the nasal cavities (i.e., space behind the vestibule of the nose), anterior nares (i.e., the opening in the nose to the nasal cavities, also referred to as the external nares), and/or nasopharynx (i.e., the portion of the pharynx, i.e., throat, that lies above the point of food entry into the pharynx) of a subject of microorganisms.
• nasal cavities i.e., space behind the vestibule of the nose
• anterior nares i.e., the opening in the nose to the nasal cavities, also referred to as the external nares
• nasopharynx i.e., the portion of the pharynx, i.e., throat, that lies above
• compositions of the present invention can also be used to decolonize microorganisms from wounds.
• compositions of the present invention are particularly useful in immunocompromised patients (including oncology patients, diabetics, HIV patients, transplant patients an the like), particularly for fungi such as Aspergillus spp. and Fusarium spp.
• compositions of the present invention can be used in chronic wounds to eliminate methicillin-resistant Staphylococcus aureus , which may or may not show clinical signs of infection such as inflammation, pus, exudate, etc. Also, it is of significance to note that certain compositions of the present invention can kill lipid-enveloped viruses, which can be very difficult to kill and can cause shingles (Herpes), chronic sinusitis, otitis media, and other local diseases.
• compositions of the present invention provides antimicrobial activity using assay and bacterial screening methods well known in the art.
• One readily performed assay involves exposing selected known or readily available viable microorganism strains, such as Enterococcus spp., Aspergillus spp., Escherichia spp., Staphylococcus spp., Streptococcus spp., Pseudomonas spp., or Salmonella spp., to a test composition at a predetermined bacterial burden level in a culture media at an appropriate temperature. For the preferred compositions of the present invention this is most conveniently done by the Antimicrobial Kill Rate Test described in the Examples Section.
• Bacterial reduction is generally reported as log 10 reduction determined by the difference between the log 10 of the initial inoculum count and the log 10 of the inoculum count after exposure.
• Preferred compositions of the present invention have an average of at least a 4 log reduction in test bacteria in 10 minutes.
• compositions of the present invention also exhibit very rapid antimicrobial activity. As shown in the Examples Section, preferred formulations are able to achieve an average log reduction of at least 4 log against these three organisms after a 10 minute exposure and preferably after a 5 minute exposure. More preferred compositions are able to achieve an average log reduction of at least 5 log and even more preferred at least 6 log against these three organisms after a 10 minute exposure and preferably after a 5 minute exposure.
• compositions of the present invention preferably maintain an average log reduction of at least 1 log, more preferably at least 1.5 log, and even more preferably at least 2 log, for at least 0.5 hour, more preferably at least 1 hour, and even more preferably at least 3 hours after application to an affected site or after testing the composition on the forearm of a subject.
• a composition was applied to the forearm of a subject as a uniform wet coating in an amount of approximately 4 milligrams per square centimeter (mg/cm 2 ) to the forearm of a healthy subject and allowed to thoroughly dry (typically a minimum of 10 minutes) over an area of approximately 5 ⁇ 5 cm. The dried composition was gently washed with 23° C.
• saline normal saline (0.9% by weight sodium chloride).
• the saline washed site was exposed to a known quantity of bacteria in an innoculum of about 10 6 bacteria/ml (typically Staphylococcus epidermidis or E. coli ) for 30 minutes.
• the bacteria were recovered and treated with an effective neutralizer and incubated to quantify the bacteria remaining.
• Particularly preferred compositions retain at least 1 log reduction and preferably at least 2 log reduction of bacteria after a gentle rinse with 500 ml saline.
• compositions of the present invention have a very low potential for generating microbial resistance.
• preferred compositions of the present invention have an increase in the ratio of final to initial MIC levels (i.e., minimum inhibitory concentration) of less than 16, more preferably less than 8, and even more preferably less than 4.
• minimum inhibitory concentration i.e., minimum inhibitory concentration
• compositions of the present invention have a generally low irritation level for skin, skin lesions, and mucosal membranes (including the anterior nares, nasal cavities, nasopharangyl cavity and other portions of the upper respiratory tract).
• certain preferred compositions of the present invention are no more irritating than BACTROBAN ointment (on skin) or BACTROBAN NASAL (in the anterior nares) products available from Glaxo Smith Kline.
• compositions of the present invention are substantive for relatively long periods of time to ensure adequate efficacy.
• certain compositions of the present invention remain at the site of application with antimicrobial activity for at least 4 hours and more preferably at least 8 hours.
• compositions of the present invention are physically stable.
• “physically stable” compositions are those that do not significantly change due to substantial precipitation, crystallization, phase separation, and the like, from their original condition during storage at 23° C. for at least 3 months, and preferably for at least 6 months.
• Particularly preferred compositions are physically stable if a 10-milliliter (10-ml) sample of the composition when placed in a 15-ml conical-shaped graduated plastic centrifuge tube (Corning) and centrifuged at 3,000 revolutions per minute (rpm) for 10 minutes using a Labofuge B, model 2650 manufactured by Heraeus Sepatech GmbH, Osterode, West Germany has no visible phase separation in the bottom or top of the tube.
• Preferred compositions of the present invention exhibit good chemical stability. This can be especially a concern with the antimicrobial fatty acid esters, which can often undergo transesterification, for example.
• Preferred compositions retain at least 85%, more preferably at least 90%, even more preferably at least 92%, and even more preferably at least 95%, of the antimicrobial lipid component after aging for 4 weeks at 40° C. (an average of three samples) beyond the initial 5-day equilibration period at 23° C.
• the most preferred compositions retain an average of at least 97% of the antimicrobial lipid component after aging for 4 weeks at 40° C. in a sealed container beyond the initial 5-day equilibration period at 23° C.
• the percent retention is understood to mean the weight percent of antimicrobial lipid component retained. This is determined by comparing the amount remaining in a sample aged (i.e., aged beyond the initial 5-day equilibration period) in a sealed container that does not cause degradation, to the actual measured level in an identically prepared sample (preferably from the same batch) and allowed to sit at 23° C. for five days.
• the level of antimicrobial lipid component is preferably determined using gas chromatography as described in the Aging Study Using Gas Chromatography test method included in the Examples Section.
• the antimicrobial lipid component is that component of the composition that provides at least part of the antimicrobial activity. That is, the antimicrobial lipid component has at least some antimicrobial activity for at least one microorganism. It is generally considered the main active component of the compositions of the present invention.
• the antimicrobial lipid component includes one or more fatty acid esters of a polyhydric alcohol, fatty ethers of a polyhydric alcohol, or alkoxylated derivatives thereof (of either or both of the ester and ether), or combinations thereof.
• the antimicrobial component is selected from the group consisting of a (C8-C12)saturated fatty acid ester of a polyhydric alcohol, a (C12-C22)unsaturated fatty acid ester of a polyhydric alcohol, a (C8-C12)saturated fatty ether of a polyhydric alcohol, a (C12-C22)unsaturated fatty ether of a polyhydric alcohol, an alkoxylated derivative thereof, and combinations thereof.
• the esters and ethers are monoesters and monoethers, unless they are esters and ethers of sucrose in which case they can be monoesters, diesters, monoethers, or monoethers. Various combinations of monoesters, diesters, monoethers, and diethers can be used in a composition of the present invention.
• the R 2 group includes at least one free hydroxyl group (preferably, residues of glycerin, propylene glycol, or sucrose).
• Preferred fatty acid esters of polyhydric alcohols are esters derived from C8, C10, and C12 saturated fatty acids.
• Exemplary fatty acid monoesters include, but are not limited to, glycerol monoesters of lauric (monolaurin), caprylic (monocaprylin), and capric (monocaprin) acid, and propylene glycol monoesters of lauric, caprylic, and capric acid, as well as lauric, caprylic, and capric acid monoesters of sucrose.
• Other fatty acid monoesters include glycerin and propylene glycol monoesters of oleic (18:1), linoleic (18:2), linolenic (18:3), and arachonic (20:4)unsaturated (including polyunsaturated) fatty acids.
• the fatty acid monoesters that are suitable for use in the present composition include known monoesters of lauric, caprylic, and capric acid, such as that known as GML or the trade designation LAURICIDIN (the glycerol monoester of lauric acid commonly referred to as monolaurin or glycerol monolaurate), glycerol monocaprate, glycerol monocaprylate, propylene glycol monolaurate, propylene glycol monocaprate, propylene glycol monocaprylate, and combinations thereof.
• LAURICIDIN the glycerol monoester of lauric acid commonly referred to as monolaurin or glycerol monolaurate
• glycerol monocaprate the glycerol monocaprate
• propylene glycol monolaurate propylene glycol monocaprate
• propylene glycol monocaprylate propylene glycol monocaprylate
• Exemplary fatty acid diesters of sucrose include, but are not limited to, lauric, caprylic, and capric diesters of sucrose as well as combinations thereof.
• Preferred fatty ethers are monoethers of (C8-C12)alkyl groups.
• Exemplary fatty monoethers include, but are not limited to, laurylglyceryl ether, caprylglycerylether, caprylylglyceryl ether, laurylpropylene glycol ether, caprylpropyleneglycol ether, and caprylylpropyleneglycol ether.
• Other fatty monoethers include glycerin and propylene glycol monoethers of oleyl (18:1), linoleyl (18:2), linolenyl (18:3), and arachonyl (20:4)unsaturated and polyunsaturated fatty alcohols.
• the fatty monoethers that are suitable for use in the present composition include laurylglyceryl ether, caprylglycerylether, caprylyl glyceryl ether, laurylpropylene glycol ether, caprylpropyleneglycol ether, caprylylpropyleneglycol ether, and combinations thereof.
• alkoxylated derivatives of the aforementioned fatty acid esters and fatty ethers also have antimicrobial activity as long as the total alkoxylate is kept relatively low.
• Preferred alkoxylation levels are disclosed in U.S. Pat. No. 5,208,257 (Kabara).
• the total moles of ethylene oxide is preferably less than 5, and more preferably less than 2.
• the fatty acid esters or fatty ethers of polyhydric alcohols can be alkoxylated, preferably ethoxylated and/or propoxylated, by conventional techniques.
• Alkoxylating compounds are preferably selected from the group consisting of ethylene oxide, propylene oxide, and mixtures thereof, and similar oxirane compounds.
• compositions of the present invention include one or more fatty acid esters, fatty ethers, alkoxylated fatty acid esters, or alkoxylated fatty ethers at a suitable level to produce the desired result.
• Such compositions preferably include a total amount of such material of at least 0.01 percent by weight (wt-%), more preferably at least 0.1 wt-%, even more preferably at least 0.25 wt-%, even more preferably at least 0.5 wt-%, and even more preferably at least 1 wt-%, based on the total weight of the “ready to use” or “as used” composition.
• compositions are present in a total amount of no greater than 20 wt-%, more preferably no greater than 15 wt-%, even more preferably no greater than 10 wt-%, and even more preferably no greater than 5 wt-%, based on the “ready to use” or “as used” composition. Certain compositions may be higher in concentration if they are intended to be diluted prior to use.
• compositions of the present invention that include one or more fatty acid monoesters, fatty monoethers, or alkoxylated derivatives thereof can also include a small amount of a di- or tri-fatty acid ester (i.e., a fatty acid di- or tri-ester), a di- or tri-fatty ether (i.e., a fatty di- or tri-ether), or alkoxylated derivative thereof.
• a di- or tri-fatty acid ester i.e., a fatty acid di- or tri-ester
• a di- or tri-fatty ether i.e., a fatty di- or tri-ether
• such components are present in an amount of no more than 50 wt-%, more preferably no more than 40 wt-%, even more preferably no more than 25 wt-%, even more preferably no more than 15 wt-%, even more preferably no more than 10 wt-%, even more preferably no more than 7 wt-%, even more preferably no more than 6 wt-%, and even more preferably no more than 5 wt-%, based on the total weight of the antimicrobial lipid component.
• glycerin for monoesters, monoethers, or alkoxylated derivatives of glycerin, preferably there is no more than 15 wt-%, more preferably no more than 10 wt-%, even more preferably no more than 7 wt-%, even more preferably no more than 6 wt-%, and even more preferably no more than 5 wt-% of a diester, diether, triester, triether, or alkoxylated derivatives thereof present, based on the total weight of the antimicrobial lipid components present in the composition.
• higher concentrations of di- and tri-esters may be tolerated in the raw material if the formulation initially includes free glycerin because of transesterification reactions.
• compositions of the present invention include an enhancer (preferably a synergist) to enhance the antimicrobial activity especially against Gram negative bacteria, such as E. coli .
• the enhancer component may include an alpha-hydroxy acid, a beta-hydroxy acid, other carboxylic acids, a (C1-C4)alkyl carboxylic acid, a (C6-C12)aryl carboxylic acid, a (C6-C12)aralkyl carboxylic acid, a (C6-C12)alkaryl carboxylic acid, a phenolic compound (such as certain antioxidants and parabens), a (C1-C10)monohydroxy alcohol, or a glycol ether (i.e., ether glycol).
• a glycol ether i.e., ether glycol
• the alpha-hydroxy acid, beta-hydroxy acid, and other carboxylic acid enhancers are preferably present in their protonated, free acid form. It is not necessary for all of the acidic enhancers to be present in the free acid form, however, the preferred concentrations listed below refer to the amount present in the free acid form.
• the chelator enhancers that include carboxylic acid groups are preferably present with at least one, and more preferably at least two, carboxylic acid groups in their free acid form. The concentrations given below assume this to be the case.
• One or more enhancers may be used in the compositions of the present invention at a suitable level to produce the desired result. In a preferred embodiment, they are present in a total amount of at least 0.01 wt-%, based on the total weight of the ready to use composition. In a preferred embodiment, they are present in a total amount of no greater than 20 wt-%, based on the total weight of the ready to use composition.
• concentrations typically apply to alpha-hydroxy acids, beta-hydroxy acids, other carboxylic acids, chelating agents, phenolics, ether glycols, (C5-C10)monohydroxy alcohols. Generally, higher concentrations are needed for (C1-C4)monohydroxy alcohols, as described in greater detail below.
• the total concentration of the enhancer component relative to the total concentration of the antimicrobial lipid component is preferably within a range of 10:1 to 1:300, and more preferably 5:1 and 1:10, on a weight basis.
• an enhancer is the solubility and physical stability in the compositions. Many of the enhancers discussed herein are insoluble in preferred hydrophobic components such as petrolatum. It has been found that the addition of a minor amount (typically less than 30 wt-%, preferably less than 20 wt-%, and more preferably less than 12 wt-%) of a hydrophilic component not only helps dissolve and physically stabilize the composition but improves the antimicrobial activity as well. These hydrophilic components are described below.
• alpha-hydroxy acids include, but are not limited to, lactic acid, malic acid, citric acid, 2-hydroxybutanoic acid, 3-hydroxybutanoic acid, mandelic acid, gluconic acid, glycolic acid, tartaric acid, alpha-hydroxyethanoic acid, ascorbic acid, alpha-hydroxyoctanoic acid, hydroxycaprylic acid, as well as derivatives thereof (e.g., compounds substituted with hydroxyls, phenyl groups, hydroxyphenyl groups, alkyl groups, halogens, as well as combinations thereof).
• Preferred alpha-hydroxy acids include lactic acid, malic acid, and mandelic acid.
• acids may be in D, L, or DL form and may be present as free acid, lactone, or partial salts thereof. All such forms are encompassed by the term “acid.” Preferably, the acids are present in the free acid form.
• the alpha-hydroxy acids useful in the compositions of the present invention are selected from the group consisting of lactic acid, mandelic acid, and malic acid, and mixtures thereof. Other suitable alpha-hydroxy acids are described in U.S. Pat. No. 5,665,776 (Yu).
• One or more alpha-hydroxy acids may be used in the compositions of the present invention at a suitable level to produce the desired result.
• they are present in a total amount of at least 0.25 wt-%, more preferably, at least 0.5 wt-%, and even more preferably, at least 1 wt-%, based on the total weight of the ready to use composition.
• they are present in a total amount of no greater than 10 wt-%, more preferably, no greater than 5 wt-%, and even more preferably, no greater than 3 wt-%, based on the total weight of the ready to use composition. Higher concentrations may become irritating.
• the ratio of alpha-hydroxy acid enhancer to total antimicrobial lipid component is preferably at most 10:1, more preferably at most 5:1, and even more preferably at most 1:1.
• the ratio of alpha-hydroxy acid enhancer to total antimicrobial lipid component is preferably at least 1:20, more preferably at least 1:12, and even more preferably at least 1:5.
• Preferably the ratio of alpha-hydroxy acid enhancer to total antimicrobial lipid component is within a range of 1:12 to 1:1.
• beta-hydroxy acids include, but are not limited to, salicylic acid, beta-hydroxybutanoic acid, tropic acid, and trethocanic acid.
• the beta-hydroxy acids useful in the compositions of the present invention are selected from the group consisting of salicylic acid, beta-hydroxybutanoic acid, and mixtures thereof.
• Other suitable beta-hydroxy acids are described in U.S. Pat. No. 5,665,776 (Yu).
• One or more beta-hydroxy acids may be used in the compositions of the present invention at a suitable level to produce the desired result.
• they are present in a total amount of at least 0.1 wt-%, more preferably at least 0.25 wt-%, and even more preferably at least 0.5 wt-%, based on the total weight of the ready to use composition.
• they are present in a total amount of no greater than 10 wt-%, more preferably no greater than 5 wt-%, and even more preferably no greater than 3 wt-%, based on the total weight of the ready to use composition. Higher concentrations may become irritating.
• the ratio of beta-hydroxy acid enhancer to total antimicrobial lipid component is preferably at most 10:1, more preferably at most 5:1, and even more preferably at most 1:1.
• the ratio of beta-hydroxy acid enhancer to total antimicrobial lipid component is preferably at least 1:20, more preferably at least 1:15, and even more preferably at least 1:10.
• Preferably the ratio of beta-hydroxy acid enhancer to total antimicrobial lipid component is within a range of 1:15 to 1:1.
• transesterification may be the principle route of loss of the Fatty Acid MonoEster (FAME), Fatty AlkylMonoETHer (FAMEth), and alkoxylated derivatives of these active ingredients.
• FAME Fatty Acid MonoEster
• FAMEth Fatty AlkylMonoETHer
• alkoxylated derivatives of these active ingredients include alpha-hydroxy acids (AHA) and beta-hydroxy acids (BHA) since these are believed to be less likely to transesterify the ester antimicrobial lipid or other ester by reaction of the hydroxyl group of the AHA or BHA.
• salicylic acid may be particularly preferred in certain formulations since the phenolic hydroxyl group is a much more acidic alcohol and thus much less likely to react.
• Other particularly preferred compounds in anhydrous or low-water content formulations include lactic, mandelic, malic, citric, tartaric, and glycolic acid.
• Carboxylic acids other than alpha- and beta-carboxylic acids are suitable for use in the enhancer component. These include alkyl, aryl, aralkyl, or alkaryl carboxylic acids typically having equal to or less than 12 carbon atoms.
• the carboxylic acid is a (C1-C4)alkyl carboxylic acid, a (C6-C12)aralkyl carboxylic acid, or a (C6-C12)alkaryl carboxylic acid.
• Exemplary acids include, but are not limited to, acetic acid, propionic acid, benzoic acid, benzylic acid, nonylbenzoic acid, and the like. Particularly preferred is benzoic acid.
• One or more carboxylic acids may be used in the compositions of the present invention at a suitable level to produce the desired result.
• they are present in a total amount of at least 0.1 wt-%, more preferably at least 0.25 wt-%, even more preferably at least 0.5 wt-%, and most preferably at least 1 wt-%, based on the ready to use concentration composition.
• they are present in a total amount of no greater than 10 wt-%, more preferably no greater than 5 wt-%, and even more preferably no greater than 3 wt-%, based on the ready to use composition.
• the ratio of the total concentration of carboxylic acids (other than alpha- or beta-hydroxy acids) to the total concentration of the antimicrobial lipid component is preferably within a range of 10:1 to 1:100, and more preferably 2:1 to 1:10, on a weight basis.
• a chelating agent is typically an organic compound capable of multiple coordination sites with a metal ion in solution. Typically these chelating agents are polyanionic compounds and coordinate best with polyvalent metal ions. Exemplary chelating agents include, but are not limited to, ethylene diamine tetraacetic acid (EDTA) and salts thereof (e.g., EDTA(Na) 2 , EDTA(Na) 4 , EDTA(Ca), EDTA(K) 2 ), sodium acid pyrophosphate, acidic sodium hexametaphosphate, adipic acid, succinic acid, polyphosphoric acid, sodium acid pyrophosphate, sodium hexametaphosphate, acidified sodium hexametaphosphate, nitrilotris(methylenephosphonic acid), diethylenetriaminepentaacetic acid, 1-hydroxyethylene, 1,1-diphosphonic acid, and diethylenetriaminepenta-(methylenephosphonic acid
• the chelating agents useful in the compositions of the present invention include those selected from the group consisting of ethylenediaminetetraacetic acid and salts thereof, succinic acid, and mixtures thereof.
• ethylenediaminetetraacetic acid and salts thereof Preferably, either the free acid or the mono- or di-salt form of EDTA is used.
• One or more chelating agents may be used in the compositions of the present invention at a suitable level to produce the desired result.
• they are present in a total amount of at least 0.01 wt-%, more preferably at least 0.05 wt-%, even more preferably at least 0.1 wt-%, and even more preferably at least 1 wt-%, based on the weight of the ready to use composition.
• they are present in a total amount of no greater than 10 wt-%, more preferably no greater than 5 wt-%, and even more preferably no greater than 1 wt-%, based on the weight of the ready to use composition.
• the ratio of the total concentration of chelating agents (other than alpha- or beta-hydroxy acids) to the total concentration of the antimicrobial lipid component is preferably within a range of 10:1 to 1:100, and more preferably 1:1 to 1:10, on a weight basis.
• a phenolic compound enhancer is typically a compound having the following general structure: wherein: m is 0 to 3 (especially 1 to 3), n is 1 to 3 (especially 1 to 2), each R 12 independently is alkyl or alkenyl of up to 12 carbon atoms (especially up to 8 carbon atoms) optionally substituted with 0 in or on the chain (e.g., as a carbonyl group) or OH on the chain, and each R 13 independently is H or alkyl or alkenyl of up to 8 carbon atoms (especially up to 6 carbon atoms) optionally substituted with 0 in or on the chain (e.g., as a carbonyl group) or OH on the chain, but where R 13 is H, n preferably is 1 or 2.
• phenolic enhancers include, but are not limited to, butylated hydroxy anisole, e.g., 3(2)-tert-butyl-4-methoxyphenol (BHA), 2,6-di-tert-butyl-4-methylphenol (BHT), 3,5-di-tert-butyl-4-hydroxybenzylphenol, 2,6-di-tert-4-hexylphenol, 2,6-di-tert-4-octylphenol, 2,6-di-tert-4-decylphenol, 2,6-di-tert-butyl-4-ethylphenol, 2,6-di-tert-4-butylphenol, 2,5-di-tert-butylphenol, 3,5-di-tert-butylphenol, 4,6-di-tert-butyl-resorcinol, methyl paraben (4-hydroxybenzoic acid methyl ester), ethyl paraben, propyl paraben, butyl
• Some of the preferred phenolic synergists are BHA, BHT, methyl paraben, ethyl paraben, propyl paraben, and butyl paraben as well as combinations of these.
• One or more phenolic compounds may be used in the compositions of the present invention at a suitable level to produce the desired result.
• concentrations of the phenolic compounds in medical-grade compositions may vary widely, but as little as 0.001 wt-%, based on the total weight of the composition, can be effective when the above-described esters are present within the above-noted ranges.
• they are present in a total amount of at least 0.01 wt-%, more preferably at least 0.10 wt-%, and even more preferably at least 0.25 wt-%, based on the ready to use composition.
• they are present in a total amount of no greater than 8 wt-%, more preferably no greater than 4 wt-%, and even more preferably no greater than 2 wt-%, based on the ready to use composition.
• the ratio of the total phenolic concentration to the total concentration of the antimicrobial lipid component be within a range of 10:1 to 1:300, and more preferably within a range of 1:1 to 1:10, on a weight basis.
• concentrations of the phenolics are normally observed unless concentrated formulations for subsequent dilution are intended.
• concentrations of the phenolics and the antimicrobial lipid components to provide an antimicrobial effect will vary with the particular application.
• An additional enhancer is a monohydroxy alcohol having 1-10 carbon atoms. This includes the lower (i.e., C1-C4) monohydroxy alcohols (e.g., methanol, ethanol, isopropanol, and butanol) as well as longer chain (i.e., C5-C10) monohydroxy alcohols (e.g., iosbutanol, t-butanol, octanol, and decanol).
• the alcohols useful in the compositions of the present invention are selected from the group consisting of methanol, ethanol, isopropyl alcohol, and mixtures thereof.
• One or more alcohols may be used in the compositions of the present invention at a suitable level to produce the desired result.
• the short chain (i.e., C1-C4) alcohols are present in a total amount of at least 10 wt-%, even more preferably at least 15 wt-%, even more preferably at least 20 wt-%, and even more preferably at least 25 wt-%, based on the total weight of the ready to use composition.
• the (C1-C4)alcohols are present in a total amount of no greater than 90 wt-%, more preferably no greater than 70 wt-%, and even more preferably no greater than 60 wt-%, based on the total weight of the ready to use composition.
• longer chain (i.e., C5-C10) alcohols are present in a total amount of at least 0.1 wt-%, more preferably at least 0.25 wt-%, and even more preferably at least 0.5 wt-%, and most preferably at least 1.0%, based on the ready to use composition.
• the (C6-C10)alcohols are present in a total amount of no greater than 10 wt-%, more preferably no greater than 5 wt-%, and even more preferably no greater than 2 wt-%, based on the total weight of the ready to use composition.
• Ether glycols An additional enhancer is an ether glycol.
• Examples include dipropylene glycol, triethylene glycol, the line of products available under the trade designation DOWANOL DB (di(ethylene glycol)butyl ether), DOWANOL DPM (di(propylene glycol)monomethyl ether), and DOWANOL TPnB (tri(propylene glycol)monobutyl ether), as well as many others available from Dow Chemical, Midland Mich.
• DOWANOL DB di(ethylene glycol)butyl ether
• DOWANOL DPM di(propylene glycol)monomethyl ether
• DOWANOL TPnB tri(propylene glycol)monobutyl ether
• One or more ether glycols may be used in the compositions of the present invention at a suitable level to produce the desired result. In a preferred embodiment, they are present in a total amount of at least 0.01 wt-%, based on the total weight of the ready to use composition. In a preferred embodiment, they are present in a total amount of no greater than 20 wt-%, based on the total weight of the ready to use composition.
• compositions of the present invention can include one or more surfactants to emulsify the composition and to help wet the surface to aid in contacting the microorganisms.
• surfactant means an amphiphile (a molecule possessing both polar and nonpolar regions which are covalently bound) capable of reducing the surface tension of water and/or the interfacial tension between water and an immiscible liquid.
• the term is meant to include soaps, detergents, emulsifiers, surface active agents and the like.
• the surfactant can be cationic, anionic, nonionic, or amphoteric.
• Preferred surfactants are those that have an HLB (i.e., hydrophile to lipophile balance) of at least 4 and more preferably at least 8. Even more preferred surfactants have an HLB of at least 12. Most preferred surfactants have an HLB of at least 15.
• HLB hydrophile to lipophile balance
• the surfactants useful in the compositions of the present invention are selected from the group consisting of sulfonates, sulfates, phosphonates, phosphates, poloxamer (polyethylene oxide/polypropylene oxide block copolymers), cationic surfactants, and mixtures thereof.
• the surfactants useful in the compositions of the present invention are selected from the group consisting of sulfonates, sulfates, phosphates, and mixtures thereof.
• One or more surfactants may be used in the compositions of the present invention at a suitable level to produce the desired result.
• they are present in a total amount of at least 0.1 wt-%, more preferably at least 0.5 wt-%, and even more preferably at least 1.0 wt-%, based on the total weight of the ready to use composition.
• they are present in a total amount of no greater than 10 wt-%, more preferably no greater than 5 wt-%, and even more preferably no greater than 2 wt-%, based on the total weight of the ready to use composition.
• the ratio of the total concentration of surfactant to the total concentration of the antimicrobial lipid component is preferably within a range of 5:1 to 1:100, more preferably 3:1 to 1:10, and most preferably 2:1 to 1:3, on a weight basis.
• Cationic Surfactants include, but are not limited to, salts of optionally polyoxyalkylenated primary, secondary, or tertiary fatty amines; quaternary ammonium salts such as tetraalkylammonium, alkylamidoalkyltrialkylammonium, trialkylbenzylammonium, trialkylhydroxyalkylammonium, or alkylpyridinium halides (preferably chlorides or bromides); imidazoline derivatives; amine oxides of a cationic nature (e.g., at an acidic pH).
• the cationic surfactants useful in the compositions of the present invention are selected from the group consisting of tetralkyl ammonium, trialkylbenzylammonium, and alkylpyridinium halides, and mixtures thereof.
• amine oxide surfactants including alkyl and alkylamidoalkyldialkylamine oxides of the following formula: (R 14 ) 3 —N ⁇ O wherein R 14 is a (C1-C30)alkyl group (preferably a (C1-C14)alkyl group) or a (C6-C18)aralklyl or alkaryl group, wherein any of these groups can be optionally substituted in or on the chain by N-, O-, or S-containing groups such as amide, ester, hydroxyl, and the like.
• Each R 14 may be the same or different provided at least one R 14 group includes at least eight carbons.
• the R 14 groups can be joined to form a heterocyclic ring with the nitrogen to form surfactants such as amine oxides of alkyl morpholine, alkyl piperazine, and the like.
• surfactants such as amine oxides of alkyl morpholine, alkyl piperazine, and the like.
• two R 14 groups are methyl and one R 14 group is a (C12-C16)alkyl or alkylamidopropyl group.
• amine oxide surfactants include those commercially available under the trade designations AMMONYX LO, LMDO, and CO, which are lauryldimethylamine oxide, laurylamidopropyldimethylamine oxide, and cetyl amine oxide, all from Stepan Company.
• anionic surfactants include, but are not limited to, sarcosinates, glutamates, alkyl sulfates, sodium alkyleth sulfates, ammonium alkyleth sulfates, ammonium laureth-n-sulfates, laureth-n-sulfates, isethionates, glycerylether sulfonates, sulfosuccinates, alkylglyceryl ether sulfonates, alkyl phosphates, aralkyl phosphates, alkylphosphonates, and aralkylphosphonates.
• anionic surfactants may have a metal or organic ammonium counterion.
• the anionic surfactants useful in the compositions of the present invention are selected from the group consisting of:
• Suitable anionic surfactants include sulfonates and sulfates such as alkyl sulfates, alkylether sulfates, alkyl sulfonates, alkylether sulfonates, alkylbenzene sufonates, alkylbenzene ether sulfates, alkylsulfoacetates, secondary alkane sulfonates, secondary alkylsulfates, and the like.
• R 14 includes an alkylamide group such as R 16 —C(O)N(CH 3 )CH 2 CH 2 — as well as ester groups such as —OC(O)—CH 2 — wherein R 16 is a (C8-C22)alkyl group (branched, straight, or cyclic group).
• alkane sulfonates such as Hostapur SAS which is a Sodium (C14-C17)secondary alkane sulfonates (alpha-olefin sulfonates) available from Clariant Corp., Charlotte, N.C.; methyl-2-sulfoalkyl esters such as sodium methyl-2-sulfo(C12-16)ester and disodium 2-sulfo(C12-C16)fatty acid available from Stepan Company under the trade designation ALPHASTE PC-48; alkylsulfoacetates and alkylsulfosuccinates available as sodium laurylsulfoacetate (under the trade designation LANTHANOL LAL) and disodiumlaurethsulfosuccinate (STEPANMILD SL3), both from Stepan Company; alkylsulfates such as ammoni
• Suitable anionic surfactants also include phosphates such as alkyl phosphates, alkylether phosphates, aralkylphosphates, and aralkylether phosphates.
• the ethylene oxide groups i.e., the “n” groups
• propylene oxide groups i.e., the “p” groups
• examples include a mixture of mono-, di- and tri-(alkyltetraglycolether)-o-phosphoric acid esters generally referred to as trilaureth-4-phosphate commercially available under the trade designation HOSTAPHAT 340KL from Clariant Corp., as well as PPG-5 ceteth 10 phosphate available under the trade designation CRODAPHOS SG from Croda Inc., Parsipanny, N.J., and mixtures thereof.
• trilaureth-4-phosphate commercially available under the trade designation HOSTAPHAT 340KL from Clariant Corp.
• PPG-5 ceteth 10 phosphate available under the trade designation CRODAPHOS SG from Croda Inc., Parsipanny, N.J., and mixtures thereof.
• Surfactants of the amphoteric type include surfactants having tertiary amine groups, which may be protonated, as well as quaternary amine containing zwitterionic surfactants. Those that have been particularly useful include:
• R 17 is a (C7-C21)alkyl group (saturated straight, branched, or cyclic group), a (C6-C22)aryl group, or a (C6-C22)aralkyl or alkaryl group (saturated straight, branched, or cyclic alkyl group), wherein R 17 may be optionally substituted with one or more N, O, or S atoms, or one or more hydroxyl, carboxyl, amide, or amine groups; R 19 is H or a (C1-C8)alkyl group (saturated straight, branched, or cyclic group), wherein R 19 may be optionally substituted with one or more N, O, or
• R 17 is a (C1-C18)alkyl group
• R 19 is a (C1-C2)alkyl group preferably substituted with a methyl or benzyl group and most preferably with a methyl group.
• R 19 is H it is understood that the surfactant at higher pH values could exist as a tertiary amine with a cationic counterion such as Na, K, Li, or a quaternary amine group.
• amphoteric surfactants include, but are not limited to: certain betaines such as cocobetaine and cocamidopropyl betaine (commercially available under the trade designations MACKAM CB-35 and MACKAM L from McIntyre Group Ltd., University Park, Ill.); monoacetates such as sodium lauroamphoacetate; diacetates such as disodium lauroamphoacetate; amino- and alkylamino-propionates such as lauraminopropionic acid (commercially available under the trade designations MACKAM 1L, MACKAM 2L, and MACKAM 151L, respectively, from McIntyre Group Ltd.).
• betaines such as cocobetaine and cocamidopropyl betaine
• monoacetates such as sodium lauroamphoacetate
• diacetates such as disodium lauroamphoacetate
• amino- and alkylamino-propionates such as lauraminopropionic acid
• Ammonium Sulfonate Amphoterics This class of amphoteric surfactants are often referred to as “sultaines” or “sulfobetaines” and can be represented by the following formula R 17 —(C(O)—NH) a —R 18 —N + (R 19 ) 2 —R 20 —SO 3 ⁇ wherein R 17 -R 20 and “a” are defined above. Examples include cocamidopropylhydroxysultaine (commercially available as MACKAM 50-SB from McIntyre Group Ltd.). The sulfoamphoterics may be preferred over the carboxylate amphoterics since the sulfonate group will remain ionized at much lower pH values.
• Nonionic Surfactants include, but are not limited to, alkyl glucosides, alkyl polyglucosides, polyhydroxy fatty acid amides, sucrose esters, esters of fatty acids and polyhydric alcohols, fatty acid alkanolamides, ethoxylated fatty acids, ethoxylated aliphatic acids, ethoxylated fatty alcohols (e.g., octyl phenoxy polyethoxyethanol available under the trade name TRITON X-100 and nonyl phenoxy poly(ethyleneoxy)ethanol available under the trade name NONIDET P-40, both from Sigma, St.
• alkyl glucosides alkyl polyglucosides
• polyhydroxy fatty acid amides sucrose esters, esters of fatty acids and polyhydric alcohols
• fatty acid alkanolamides ethoxylated fatty acids
• ethoxylated aliphatic acids ethoxylated fatty alcohols
• ethoxylated and/or propoxylated aliphatic alcohols e.g., that available under the trade name PLURONIC F127 from Sigma
• ethoxylated glycerides ethoxylated block copolymers with ethylene diaminetetraacetic acid (EDTA)
• EDTA ethylene diaminetetraacetic acid
• ethoxylated cyclic ether adducts ethoxylated amide and imidazoline adducts
• ethoxylated amine adducts ethoxylated mercaptan adducts
• ethoxylated condensates with alkyl phenols ethoxylated nitrogen-based hydrophobes
• ethoxylated polyoxypropylenes polymeric silicones
• fluorinated surfactants e.g., those available under the trade names FLUORAD-FS 300 from Minnesota Mining and Manufacturing Co., St.
• the nonionic surfactants useful in the compositions of the present invention are selected from the group consisting of Poloxamers such as PLURONIC from BASF, sorbitan fatty acid esters, and mixtures thereof.
• compositions of the present invention can include a hydrophilic or water-soluble component to help solubilize and/or physically stabilize the enhancer component in the composition.
• the hydrophilic component can help to improve antimicrobial activity both in terms of speed of kill and extent of kill.
• Certain compositions may be solutions, emulsions (one liquid/gel/paste dispersed in another liquid/gel/paste), or dispersions (solid in liquid/paste/gel).
• a hydrophilic material is typically a compound that has a solubility in water of at least 7 wt-%, preferably at least 10 wt-%, more preferably at least 20 wt-%, even more preferably at least 25 wt-%, and even more preferably at least 40 wt-%, at 23° C. Most preferably, a hydrophilic component is infinitely miscible with water at 23° C.
• hydrophilic components include, but are not limited to, water, polyhydric alcohols, lower alkyl ethers (i.e., having a sufficiently small number of carbon atoms to meet the solubility limit above), N-methylpyrrolidone, alkyl esters (i.e., having a sufficiently small number of carbon atoms to meet the solubility limit above), and the lower monohydroxy alcohols discussed above as enhancers, as well as combinations thereof.
• a lower monohydroxy alcohol can function as both a hydrophilic compound and an enhancer.
• the hydrophilic components include polyhydric alcohols, lower alkyl ethers, and short chain esters. More preferably, the hydrophilic components include polyhydric alcohols.
• Suitable polyhydric alcohols have a molecular weight of less than 500, preferably less than 400, and more preferably less than 200.
• polyhydric alcohols include, but are not limited to, glycerol, propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol, diethylene glycol, pentaerythritol, trimethylolpropane, trimethylolethane, trimethylolbutane, sorbitol, mannitol, xylitol, pantothenol, ethylene glycol adducts of polyhydric alcohol, propylene oxide adducts of polyhydric alcohol, 1,3-butanediol, dipropylene glycol, diglycerine, polyglycerine, erythritol, sorbitan, sugars (e.g., sucrose, glucose, fructose, mannose, x
• Ethers include materials such as dimethylisosorbide, polyethylene glycol and methoxypolyethylene glycols, block and random copolymers of ethylene oxide and propylene oxide, and laureth-4.
• Alkyl esters include triacetin, methyl acetate, esters of polyethoxylated glycols, and combinations thereof.
• the hydrophilic components useful in the compositions of the present invention include those selected from the group consisting of glycols, and in particular glycerin and propylene glycol, and mixtures thereof.
• the hydrophilic component is selected to match the polyhydric alcohol portion of any fatty acid monoester of a polyhydric alcohol antimicrobial present. For example, if the antimicrobial agent was glycerolmonolaurate (monolaurin) the most preferred hydrophilic component is glycerin. In this manner, any transesterification reaction that may occur with the carrier solvent does not produce an undesirable by-product.
• hydrophilic materials may be used in the compositions of the present invention at a suitable level to produce the desired result.
• the hydrophilic component is present in a total amount of at least 0.1%, preferably at least 1 wt-%, more preferably at least 4 wt-%, and even more preferably at least 8 wt-%, based on the weight of the ready to use composition.
• the hydrophilic component is present in a total amount of no greater than 60 wt-%, more preferably no greater than 40 wt-%, and even more preferably no greater than 20 wt-%, based on the ready to use composition.
• the hydrophilic component is present in the greatest amount it is referred to as a “vehicle.”
• water is preferably present in an amount of less than 10 wt-%, more preferably less than 5 wt-%, and even more preferably less than 2 wt-%, based on the ready to use composition.
• water can be used in a much greater amount, and can even be the primary component, as long as the composition is highly viscous.
• such highly viscous compositions have a viscosity of at least 500 centipoise (cps), more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even as high as about 500,000 cps, 1,000,000 cps, or more).
• the viscosity can be measured as described below in the Viscosity Test.
• compositions of the present invention also include one or more hydrophobic materials.
• a hydrophobic material is typically an organic compound, which at 23° C. is a liquid, gelatinous, semisolid or solid and has a solubility in water of less than 5% by weight, preferably less than 1% by weight, more preferably less than 0.5% by weight, and even more preferably less than 0.1% by weight.
• These materials include compounds typically considered emollients in the cosmetic art.
• Examples of general emollients 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 and polyethoxylated derivatives of the alcohols; 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 glycerol, pentaerythritol, ethylene glycol, propylene glycol, as well as polyethoxylated derivatives of these; (C12-C22)alkyl esters or (C12-C22)ethers of polypropylene glycol; (C12-C
• hydrophobic components include cyclic dimethicones, polydialkylsiloxanes, polyaryl/alkylsiloxanes, silicone copolyols, long chain (i.e., C8-C36)alkyl and alkenyl esters of long (i.e., C8-C18) straight or branched chain alkyl or alkenyl alcohols or acids, long chain (i.e., C8-C36)alkyl and alkenyl amides of long straight or branched chain (i.e., C8-C36)alkyl or alkenyl amines or acids; hydrocarbons including straight and branched chain alkanes and alkenes such as squalene, and mineral oil, polysiloxane polyalkylene copolymers, dialkoxy dimethyl polysiloxanes; (C12-C22)alkyl and (C12-C22)alkenyl alcohols, and petroleum derived alkanes
• the hydrophobic components useful in the compositions of the present invention include those selected from the group consisting of petrolatum USP and 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 and polyethoxylated derivatives of the alcohols; 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 (such as diisopropyladipate, diisopropylsebacate); (C1-C9)alkyl or (C6-C12)aryl esters of glycerol, pentaerythritol, ethylene glycol, propylene glycol (such as glyceryl tricap
• One or more hydrophobic materials may be used in the compositions of the present invention at a suitable level to produce the desired result.
• the hydrophobic component is present in a total amount of at least 50 wt-%, more preferably at least 70 wt-%, and even more preferably at least 80 wt-%, based on the ready to use composition.
• the hydrophobic component is present in a total amount of no greater than 99 wt-%, more preferably no greater than 95 wt-%, and even more preferably no greater than 92 wt-%, based on the ready to use composition.
• the hydrophobic component is present in the greatest amount it is referred to as a “vehicle.”
• compositions of the present invention may additionally employ adjunct components conventionally found in pharmaceutical compositions in their art-established fashion and at their art-established levels.
• the compositions may contain additional compatible pharmaceutically active materials for combination therapy (such as supplementary antimicrobials, anti-parasitic agents, antipruritics, astringents, local anaesthetics, or anti-inflammatory agents), or may contain materials useful in physically formulating various dosage forms of the present invention, such as excipients, dyes, perfumes, lubricants, thickening agents, stabilizers, skin penetration enhancers, preservatives, or antioxidants.
• antiseptics disinfectants, or antibiotics
• these include, for example, addition of metals such as silver, copper, zinc; iodine and iodophors; chlorhexidine and its various salts such as chlorhexidine digluconate; polyhexamethylenebiguanide, parachlorometaxylenol, triclosan, antimicrobial quaternarly amines including polymeric quaternary amines, “azole” antifungal agents including clortrimazole, miconazole, econazole, ketoconazole, and salts thereof; and the like.
• Antibiotics such as neomycin sulfate, bacitracin, mupirocin, and the like, also may be included.
• compositions of the present invention have exceptional broad spectrum antimicrobial activity and thus are generally not terminally sterilized but if necessary may be sterilized by a variety of industry standard techniques. For example, it may be preferred to sterilize the compositions in their final packaged form using electron beam. It may also be possible to sterilize the sample by gamma radiation or heat. Other forms of sterilization may be acceptable. It may also be suitable to include preservatives in the formulation to prevent growth of certain organisms.
• Suitable preservatives include industry standard compounds such as Parabens (methyl, ethyl, propyl, isopropyl, isobutyl, etc), 2 bromo-2 nitro-1,3, diol; 5 bromo-5-nitro-1,3 dioxane, chlorbutanol, diazolidinyl urea; iodopropylnyl butylcarbamate, phenoxyethanol, halogenated cresols, methylchloroisothiazolinone and the like, as well as combinations of these compounds.
• Parabens methyl, ethyl, propyl, isopropyl, isobutyl, etc
• 2 bromo-2 nitro-1,3, diol 5 bromo-5-nitro-1,3 dioxane, chlorbutanol, diazolidinyl urea
• iodopropylnyl butylcarbamate phenoxyethanol, halogenated cresols,
• compositions of the present invention preferably adhere well to skin, mucosal tissue, and wounds, in order to deliver the antimicrobial to the intended site over a prolonged period even in the presence of perspiration, drainage (e.g., mucosal secretions), or mild lavage.
• the compositions are typically non-aqueous, although high viscosity compositions can include a large amount of water.
• the component in the greatest amount (i.e., the vehicle) in the formulations of the invention may be any conventional vehicle commonly used for topical treatment of human or animal skin.
• the formulations are typically selected from one of the following three types: (1) anhydrous or nearly anhydrous formulations with a hydrophobic vehicle (i.e., the hydrophobic component, which can include one or more hydrophobic compounds, is present in the greatest amount); (2) anhydrous or nearly anhydrous formulations with a hydrophilic vehicle (i.e., the hydrophilic component, which can include one or more hydrophilic compounds, is present in the greatest amount); and (3) highly viscous water-based formulations. These are discussed below.
• compositions include an antimicrobial lipid component in a hydrophobic vehicle in combination with surfactant(s), an enhancer component, and a small amount of a hydrophilic component.
• the enhancers are not soluble in the hydrophobic component at room temperature although they may be at elevated temperatures.
• the hydrophilic component is generally present in a sufficient amount to stabilize (preferably to solubilize) the enhancer(s) in the composition.
• the hydrophilic component also helps to stabilize many of the surfactants used in preferred formulations.
• DOSS dioctylsulfosuccinate sodium salt
• the hydrophilic component improves the antimicrobial activity. The mechanism for this is unknown; however, it may speed the release of the enhancer component and/or the antimicrobial lipid component.
• the water content of these formulations is preferably less than 10 wt-%, more preferably less than 5 wt-%, and even more preferably less than 2 wt-%, in order to minimize hydrolysis of any ester based antimicrobial lipid present.
• the antimicrobial lipid component includes an ester to use either glycerin or propylene glycol in the hydrophilic component. It is most preferred to use a hydrophilic compound that is identical to the glycol portion of the antimicrobial lipid, e.g., propylene glycol with the propylene glycol esters and glycerin with the glycerin esters. In this manner, transesterification of the antimicrobial lipid ester with the hydrophilic compound will not result in additional chemical species present.
• formulations can be relatively easily manufactured by first heating the hydrophobic component to 85° C., adding in the surfactant, hydrophilic component, and enhancer component, cooling to 65° C., and adding the antimicrobial lipid component above its melting point.
• the enhancer component can be predissolved in the hydrophilic component (optionally along with the surfactant) and added to the hydrophobic component either before or after addition of the antimicrobial lipid component. If either the antimicrobial lipid component or the hydrophobic component are solids at room temperature this is done at the minimum temperature necessary to melt all components.
• ester containing antimicrobial lipids to enhancers that include either acid or ether groups to elevated temperatures for extended periods of time should be avoided to prevent transesterification reactions (unless this is deliberate in the case of utilizing lower purity fatty acid esters in combination with glycol hydrophilic components to produce the monoesters as discussed above).
• the present invention provides methods of manufacture.
• One preferred method involves: dissolving the enhancer component in the hydrophilic component; combining the hydrophobic vehicle and the hydrophilic component with the enhancer component dissolved therein with mixing to form a mixture; optionally heating the hydrophobic vehicle to a temperature sufficient to form a pourable liquid (which for many hydrophobic vehicles this is above its melting point) before or after combining it with the hydrophilic component and enhancer component; adding the antimicrobial lipid component to the mixture; and cooling the mixture before or after adding the antimicrobial lipid component.
• the hydrophilic component may or may not be present in the formulations that include a hydrophobic vehicle.
• another preferred method of manufacture involves: combining the enhancer component and the hydrophobic vehicle with mixing to form a mixture; optionally heating the hydrophobic vehicle to a temperature sufficient to form a pourable liquid (which for many hydrophobic vehicles is above its melting point) before or after combining it with the enhancer component; adding the antimicrobial lipid component to the mixture with mixing; and cooling the mixture before or after adding the antimicrobial lipid component.
• compositions are significantly less irritating than formulations using completely hydrophilic components.
• hydrophobic components e.g., petrolatum
• hydrophilic component e.g., glycerin
• hydrophilic components e.g., PEG 400
• the viscosity of these formulations intended for use on skin or in the anterior nares is preferably relatively high to prevent excessive drainage off the treatment site.
• the viscosity is preferably at least 500 Centipoise (cps), more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even as high as about 500,000 cps, 1,000,000 cps, or more).
• the viscosity can be measured as described below in the Viscosity Test.
• the formulations intended for use on skin, anterior nares, or where drainage would be a concern are essentially gelatinous at room temperature, having a significant yield point such that they do not flow readily at temperatures below 35° C.
• the viscosity is measured using the viscosity test described herein.
• Certain gelatinous vehicles may also have a characteristic temperature at which they “melt” or begin to dramatically lose viscosity. Preferably this is higher than body temperature also to ensure that excess drainage of the composition of the treatment site does not occur. Therefore, the melting point of the composition is preferably greater than 32° C., more preferably greater than 35° C., and even more preferably greater than about 37° C. The melting point is taken as the lowest temperature at which the viscosity becomes dramatically less or is equal to or less than 100,000 cps.
• the viscosity and/or melt temperature can be enhanced by either incorporating a crystalline or semicrystalline hydrophobic carrier such as a higher melting petrolatum, addition of an insoluble filler/thixotrope, or by addition of a polymeric thickener (e.g., a polyethylene wax in a petrolatum vehicle).
• a polymeric thickener e.g., a polyethylene wax in a petrolatum vehicle.
• Polymeric thickeners may be linear, branched, or slightly crosslinked. It is important for comfort that the formulations are relatively soft and that they spread easily to allow easy application, especially over a wound, rash, or infected area or in the anterior nares.
• a particularly preferred vehicle for use on skin, in the anterior nares, or in other areas where high viscosity is desirable is white petrolatum USP having a melting point greater than 40° C.
• Antimicrobial lipid components of this invention can be formulated into a water-soluble component such as that based on the hydrophilic compounds discussed above in combination with the synergist(s) and surfactant(s). Particularly preferred are polyethylene glycols (PEGs) including blends of different molecular weight PEGs.
• a hydrophilic component i.e., the component used in the greatest amount, which can include one or more hydrophilic compounds
• the viscosity can be enhanced by either incorporating a crystalline or semicrystalline hydrophilic compound such as a PEG, addition of an insoluble filler/thixotrope, or by addition of a polymeric thickener.
• Polymeric thickeners may be linear, branched, or slightly crosslinked. It is important for comfort that the formulations are relatively soft and that they spread easily to allow easy application, especially over a wound, rash, or infected area or in the anterior nares. For this reason, a particularly preferred vehicle is based on a blend of a liquid or semi-solid PEG (PEG 400-1000) with a more crystalline PEG (PEG 1000-2000). Particularly preferred is a blend of PEG 400 with PEG 1450 in a ratio of 4:1.
• the compositions are in the form of an ointment or cream. That is, the compositions are in the form of a relatively viscous state such that they are suitable for application to nasal passageways.
• such compositions have a viscosity of at least 500 Centipoise (cps), more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even as high as about 500,000 cps, 1,000,000 cps, or more).
• the viscosity can be measured as described below in the Viscosity Test.
• Aqueous compositions of the present invention are those in which water is present in the greatest amount, thereby forming the “vehicle.”
• a relatively high viscosity be imparted to the composition to ensure that the antimicrobial composition is not rapidly dispersed off the afflicted area.
• These formulations also adhere well to tissue and thus deliver the antimicrobial to the intended site over a prolonged period even in the presence of perspiration, drainage (e.g., mucosal secretions), or mild lavage.
• a high viscosity can be imparted by a thickener system.
• the thickener system of the invention is compatible with the antimicrobial lipid composition described above in order to provide suitable antimicrobial efficacy, chemical and physical stability, acceptable cosmetic properties, and appropriate viscosity for retention in the afflicted area.
• compositions of this invention have a viscosity of at least 500 Centipoise (cps), more preferably at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even as high as about 500,000 cps, 1,000,000 cps, or more).
• the viscosity can be measured as described below in the Viscosity Test. Because certain optional ingredients, such as enhancers, hydrophilic compounds, hydrophobic compounds, and the like, may effect the viscosity (either positively or negatively), the measured viscosity is that of the final composition.
• Preferred thickener systems used in the compositions of the present invention are capable of producing viscoelastic compositions that are very stable. By varying the amount and type of thickener, the degree of elasticity can be adjusted from almost a purely viscous composition to a highly elastic and even gel-like composition. If emollients are added, increasing the elasticity and/or yield stress of the system imparts added stability to prevent separation of immiscible emollients. Excessive elasticity, however, is not preferred because an elastic composition usually does not provide a cosmetically appealing product.
• thickener systems used in the present invention are capable of achieving high viscosities at relatively low total concentrations.
• the total concentration of the thickener system is preferably less than 8 wt-%, more preferably less than 5 wt-%, and most preferably less than 3 wt-%, based on the total weight of the ready to use composition.
• the total concentration of the thickener system can be as little as 0.5 wt-%, based on the total weight of the composition.
• the total concentration of thickener system is greater than 1 wt-%, based on the total weight of the ready to use composition.
• the thickener system can include organic polymers or inorganic thixotropes such as silica gel, clays (such as betonite, laponite, hectorite, montmorrillonite and the like), as well as organically modified inorganic particulates materials, and the like.
• organic polymers or inorganic thixotropes such as silica gel, clays (such as betonite, laponite, hectorite, montmorrillonite and the like), as well as organically modified inorganic particulates materials, and the like.
• organic polymers or inorganic thixotropes such as silica gel, clays (such as betonite, laponite, hectorite, montmorrillonite and the like), as well as organically modified inorganic particulates materials, and the like.
• an organic polymer is considered part of the thickener system if its presence in the composition results in an increase in the viscosity of the composition.
• certain nonionic polymers such as lower molecular weight polyethylene glycols (e.g., those having a molecular weight of less than 20,000) do not increase the viscosity of the composition significantly. These are considered part of the hydrophilic component, for example, rather than part of the thickener system.
• the thickener system can be prepared from one or more nonionic, cationic, anionic, zwitterionic, or associative polymers as long as they are compatible with the antimicrobial lipid and enhancer components of the composition.
• certain acidic enhancers such as those that include carboxylic acid groups are most effective in their protonated form. This requires that the composition has an acidic pH. For this reason, many anionic thickeners based on neutralized carboxylic acid groups would not be suitable.
• Carbopol-type thickeners based on polyacrylic acid salts do not typically thicken well at pH values of less than 5 and certainly less than a pH of 4.5.
• the polymers are preferably based on sulfonic acid, sulfate, phosphonic acid, or phosphate groups. These polymers are able to thicken at much lower pH values due to the lower pKa of these acid groups.
• Preferred polymers of this class include ARISTOFLEX HMB (ammonium acryloyldimethyltaurate/beheneth-25 methacrylate crosspolymer) and ARISTOFLEX ASV (ammonium acryloyldimethyltaurate/NVP copolymer) from Clariant Corporation.
• Other preferred sulfonic acid polymers are those described in U.S. Pat. No. 5,318,955.
• compositions that include an acidic enhancer component are thickened using cationic or nonionic thickeners since these perform well at low pH.
• many of the nonionic and cationic polymers can tolerate higher levels of salts and other additives and still maintain high viscosity.
• nonionic polymeric thickeners include modified celluloses, guar, xanthan gum, and other natural polymers such as polysaccharides and proteins, associative polymers based on nonionic ethylenically unsaturated monomers wherein at least one comonomer has at least 16 carbon atoms, and polymers based on ethylenically unsaturated monomers selected from the group consisting of acrylates, acrylamides, vinyl lactams, vinyl acetate and its hydrolyzed derivatives, methyl vinyl ethers, styrene, and acrylonitrile.
• a preferred group of cationic polymeric thickeners include cationically modified celluloses, quaternized natural amino-functional polymers, and polymers based on ethylenically unsaturated monomers selected from the group consisting of acrylates, acrylamides, vinyl lactams, vinyl acetates, methyl vinyl ethers, styrene, and acrylonitrile.
• Cationic polymers for use in the compositions of this invention can be selected from both permanently charged quaternary polymers (those polymers with quaternary amines such as Polyquaternium 4, 10, 24, 32, and 37, described below) as well as protonated primary, secondary, and tertiary amine functional polymers that have been protonated with a suitable protonic acid.
• Preferred protonated cationic polymers are based on tertiary amines.
• the protonated cationic polymers are preferably protonated with suitable acids that will not result in undue skin irritation.
• (C1-C10)alkylcarboxylic acids optionally substituted by oxygen e.g., acetic acid, alpha-hydroxy acids such as lactic acid, gluconic acid, benzoic acid, mandelic acid, and the like
• (C1-C10)alkylsulfonic acids e.g., methylsulfonic acid and ethylsulfonic acid
• (C1-C10)alkylhydrogensulfates e.g., methylhydrogensulfate
• mineral acids e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and the like.
• the charge on protonated cationic polymers is pH dependent. For this reason, in order to ensure the polymer is sufficiently protonated, the pH is adjusted appropriately and should be in the range of preferably 2-9.5, more preferably 2-8, and most preferably 2.5-7.5.
• the pH of preferred compositions that include acidic enhancers should be lower and is typically 2-5, and preferably 2-4. It should be noted that it is not necessary to have all of the amines on a particular polymer protonated. The level of protonation will to a certain extent be pH dependent.
• the quaternary, tertiary, secondary, and primary amine functional polymers may be chosen from natural polymers, modified natural polymers, as well as synthetic polymers. These polymers may be soluble or swellable in the aqueous solvent. Furthermore, these polymers may also possess hydrophobic side chains and thus be associative polymers.
• Polymers can be classified as soluble, swellable, or associative in the aqueous compositions. Some polymers may fall into one or more of these classes. For example, certain associative polymers can be soluble in the aqeuous system. Whether they are considered soluble, swellable, or associative in the aqueous system, suitable polymers for use in the compositions of the present invention may be film forming or not. Film forming polymers may retain the active antimicrobial component at the afflicted site for longer periods of time. This may be desirable for certain applications. For example, some film forming polymers may produce compositions that could not be easily washed off with water after being applied and dried.
• a soluble polymer is one that in dilute solution (i.e., 0.01-0.1 wt-% in the desired aqueous solvent system defined as containing water and any other hydrophilic compounds), after heating for a sufficient time to ensure solubilization of any potentially soluble components, has no significant observable particles of greater than 1 micron in particle size, as determined by light scattering measurements using, for example, Malvern Masterisizer E Laser Particle Size Analyzer available from Malvern Co., Boston, Mass.
• a swellable polymer is one that in dilute solution (i.e., 0.01-0.1 wt-% in the desired aqueous solvent system), after heating for a sufficient time to ensure solubilization of any potentially soluble components, has a significant (i.e., detectable) number of observable particles of greater than 1 micron in particle size, as determined by light scattering measurements using, for example, Malvern Masterisizer E Laser Particle Size Analyzer.
• an associative polymer is one that has greater than 2 hydrophobic chains per polymer molecule of greater than 16 carbon atoms. Examples of such polymers are as follows.
• Soluble Polymers Cationic Natural Polymer Derivatives. Cationic modified cellulosic polymers are reported in the literature to be soluble in water. Such polymers have been found to be useful in the present invention.
• the most preferred modified cellulose products are sold under the trade names CELQUAT (National Starch and Chemicals Corp., Bridgewater, N.J.) and UCARE (Amerchol Corporation, Edison, N.J.).
• CELQUAT is a copolymer of a polyethoxylated cellulose and dimethyldiallyl ammonium chloride and has the Cosmetic, Toiletry and Fragrance Association (CTFA) designation Polyquaternium-4.
• alkyl modified quaternary ammonium salt of hydroxyethyl cellulose and a trimethyl ammonium chloride substituted epoxide can also be used.
• the polymer conforms to the CTFA designation Polyquaternium 24 and is commercially available as QUATRISOFT LM-200 from Amerchol Corp., Edison, N.J.
• a particularly suitable type of cationic polysaccharide polymer that can be used is a cationic guar gum derivative, such as guar hydroxypropyltrimonium chloride (Commercially available from Rhone-Poulenc under the trade designation JAGUAR).
• a cationic guar gum derivative such as guar hydroxypropyltrimonium chloride (Commercially available from Rhone-Poulenc under the trade designation JAGUAR).
• Soluble Polymers —Cationic Synthetic Polymers.
• Synthetic cationic linear polymers useful in the present invention are preferably quite high in cationic charge density—generally having greater than 10 wt-% cationic monomer, preferably greater than 25 wt-%, and more preferably greater than 50 wt-%. This ensures a good cosmetic feel and may actually improve water solubility.
• the polymers useful in the present invention have sufficient molecular weight to achieve thickening at generally less than 5 wt-% polymer, but not too high that the lotion/cream/ointment feels slimy and stringy.
• the polymers preferably have a molecular weight of at least 250,000 daltons, and more preferably at least 500,000 daltons.
• the polymers preferably have a molecular weight of no greater than 3,000,000 daltons, and more preferably no greater than 1,000,000 daltons.
• the homopolymers are preferably prepared from methacryloyloxyalkyl trialkyl ammonium salt, acryloyloxyalkyl trialkyl ammonium salt, and/or quaternized dialkylaminoalkylacrylamidine salt.
• the polymers are copolymers of at least two monomers selected from the group consisting of trialkylaminoalkyl acrylate and methacrylate salts, dialkyldiallyl ammonium salts, acrylamidoalkyltrialkyl salts, methacrylamidoalkyltrialkyl salts, and alkyl imidazolinium salts, N-vinyl pyrrolidinone, N-vinyl caprolactam, methyl vinyl ether, acrylates, methacrylates, styrene, acrylonitrile, and combinations thereof.
• a variety of quaternary copolymers of varying quaternization can be synthesized based on homo or copolymers of amino acrylates with methyl, ethyl, or propyl side chains. These monomers could also be copolymerized with other nonionic monomers including quaternary acrylic homopolymers, such as homopolymers of 2-methacryloxyethyl trimethylammonium chloride and 2-methacryloxyethyl methyl diethyl ammonium bromide; and copolymers of quaternary acrylate monomers with a water-soluble monomers, such as Petrolite Product No. Q-0043, a proprietary copolymer of a linear quaternary acrylate and acrylamide at high molecular weight (4-5 million MW).
• quaternary acrylic homopolymers such as homopolymers of 2-methacryloxyethyl trimethylammonium chloride and 2-methacryloxyethyl methyl diethyl ammonium bromid
• Another useful soluble cationic polymer is N,N-dimethylaminopropyl-N-acrylamidine (which is quaternized with diethylsulfate) bound to a block of polyacrylonitrile.
• This block copolymer is available under the trade designation Hypan QT-100 from Lipo Chemicals Inc., Paterson, N.J. It is quite effective at thickening aqueous systems and has a good cosmetic feel.
• This polymer as received however, has an objectionable amine odor. The odor could probably be masked with the proper fragrance, but is preferably removed prior to formulation (e.g., with a solvent cleaning process) so that the formulation can be supplied without fragrance.
• Suitable cationic polymers include, for example, copolymers of 1-vinyl-2-pyrrolidine and 1-vinyl-3-methyl-imidazolium salt (e.g. chloride salt), referred to in the industry by the Cosmetic, Toiletry, and Fragrance Association, (CTFA) as Polyquaternium-16.
• CTFA Cosmetic, Toiletry, and Fragrance Association
• This material is commercially available from BASF Wyandotte Corp. (Parsippany, N.J., USA) under the LUVIQUAT tradename (e.g. LUVIQUAT FC 370); copolymers of 1-vinyl-2-pyrrolidine and dimethylaminoethyl methacrylate, referred to in the industry (CTFA) as Polyquaternium-11.
• cationic diallyl quaternary ammonium-containing polymers including, for example, dimethyldiallyammonium chloride homopolymer and copolymers of acrylamide and dimethyldiallylammonium chloride, referred to in the industry (CTFA) as Polyquaternium 6 and Polyquaternium 7, respectively.
• CTFA cationic diallyl quaternary ammonium-containing polymers including, for example, dimethyldiallyammonium chloride homopolymer and copolymers of acrylamide and dimethyldiallylammonium chloride, referred to in the industry (CTFA) as Polyquaternium 6 and Polyquaternium 7, respectively.
• CTFA cationic diallyl quaternary ammonium-containing polymers including, for example, dimethyldiallyammonium chloride homopolymer and copolymers of acrylamide and dimethyldiallylammonium chloride
• Soluble Polymers-Nonionic A variety of cellulosic ethers are reported in the literature to be soluble in water. Materials in this class that are nonionic and have been shown to be useful include: methylhydroxypropylcellulose, available as BENECEL MP 943 from Aqualon, Wilmington, Del.; hydroxypropylcellulose, available as KLUCEL (LF, GF, MF, HF) from Aqualon; hydroxybutylmethylcellulose (3.5% hydroxybutyl and 30% methoxyl) from Scientific Polymer Products, Ontario, N.Y.; and hydroxyethylcelluloses, available under the trade designation NATROSOL from Aqualon.
• BENECEL MP 943 from Aqualon, Wilmington, Del.
• KLUCEL LF, GF, MF, HF
• hydroxybutylmethylcellulose 3.5% hydroxybutyl and 30% methoxyl
• Xanthan gum, guar, locust bean gum, and other polysaccharides may also be suitable. These polymers may be produced from plant sources or can be produced through microbial cell culture. Protein thickeners such as gelatin and pectin may also be useful.
• Amine oxide polymers such as those described in U.S. Pat. No. 6,123,933 and those commercially available under the trade designation DIAFORMER Z-711, Z-712, Z-731, and Z-751 from Clariant Corp. are useful. Additionally, zwitterionic polymers, such as methacryloyl ethyl betaine/acrylate copolymer that are commercially available under the trade designation DIAFORMER Z-400 from Clariant Corp. can also be used. Zwitterionic polymers described in U.S. Pat. No. 6,590,051 may also be useful.
• Carboxylic acid functional polymers including naturally occurring carboxylic acid functional polymers such as hyaluronic acid and derivatives of natural polymers such as carboxymethylcellulose, alginic acid and other alginate polymers, Fucogel (a polysaccharide consisting of three mono-saccharides, fucose, galactose, and galacturonic acid), hyaluronic acid, and the like, also may be useful.
• carboxylic acid functional polymers such as hyaluronic acid and derivatives of natural polymers such as carboxymethylcellulose, alginic acid and other alginate polymers, Fucogel (a polysaccharide consisting of three mono-saccharides, fucose, galactose, and galacturonic acid), hyaluronic acid, and the like, also may be useful.
• Synthetic polymers may also be useful, such as those based on carboxylic acid, phosphonic acid, or sulfonic acid functional monomers, including but not limited to, polymers derived from acrylic acid, methacrylic acid, maleic anhydride, itaconic anhydride, sodium AMPS (the sodium salt of 2-acrylamido-2-methylpropane sulfonic acid), sulfopropyl acrylate or methacrylate, sulphomethylated acrylamide, allyl sulphonate, sodium vinyl sulphonate, combinations thereof, or other water-soluble forms of these or other polymerizable carboxylic or sulphonic acids.
• Swellable Polymers Many swellable polymers, which are slightly crosslinked, function as viscosifiers in aqueous solvent systems. In general, these swellable polymers are preferred because they tend to be far less “slimy” going on and once the hands perspire and are exposed to water after treatment. Excessive crosslinking will result in polymers that do not swell sufficiently to increase the viscosity of the composition. In order to ensure adequate swelling, if a chemical crosslinker is used, the concentration of crosslinker is quite low, e.g., less than about 1000 parts per million (ppm), and preferably less than 500 ppm, based on the weight of the dry polymer.
• ppm parts per million
• a class of crosslinked polymers suitable for use in the compositions of the present invention include acrylamide and at least one other quaternary monomer selected from the group consisting of trialkylaminoalkylacrylate and methacrylate salts, dialkyldiallyl ammonium salts, acrylamidoalkyltrialkyl ammonium salts, methacrylamidoalkyltrialkyl ammonium salts, and monomers that include imidazolinium salts.
• comonomers may also be added including N-vinyl pyrrolidone, N-vinyl caprolactam, methyl vinyl ether, acrylates, methacrylates, styrene, and the like.
• a particularly preferred polymer is a poly(2-methacryloxyethyl trimethyl ammonium chloride) polydimethylaminoethyl methacrylate, which conforms to the CTFA designation Polyquaternium 37.
• Another preferred polymer includes acrylamide and methacryloyloxyethyl trimethyl ammonium chloride, which conforms to the CTFA designation Polyquaternium 32. These are commercially available from Allied Colloids Inc. of Suffolk, Va. as SALCARE SC95, SC96, and SC92.
• swellable polymers i.e., slightly crosslinked polymers
• polymers of N-vinyl lactams such as N-vinyl pyrrolidone
• N-vinyl pyrrolidone when exposed to gamma radiation increase in molecular weight and may actually crosslink. This crosslinking allows for more efficient thickening (less polymer required to achieve a certain viscosity) and an improved cosmetic feel.
• polymers that when exposed to gamma radiation result in crosslinking, include polymers such as LUVIQUAT HM 552 (copolymers of vinylimidazolium methochloride and vinylpyrrolidone, which conforms to the CTFA designation Polyquaternium-16), and GAFQUAT HS-100 (vinylpyrrolidone/methacrylamidopropyltrimethylammonium chloride copolymer which conforms to the CTFA designation Polyquaternium-28).
• polymers such as LUVIQUAT HM 552 (copolymers of vinylimidazolium methochloride and vinylpyrrolidone, which conforms to the CTFA designation Polyquaternium-16), and GAFQUAT HS-100 (vinylpyrrolidone/methacrylamidopropyltrimethylammonium chloride copolymer which conforms to the CTFA designation Polyquaternium-28).
• Suitable crosslinkers are multi-ethylenically unsaturated compounds wherein the ethylenic groups are vinyl groups (including substituted vinyl groups, such as isopropenyl groups), allyl groups, and/or methallyl groups, which groups are bonded to nitrogen or oxygen atoms.
• Vinyl, allyl, and methallyl groups, as used herein, include substituted derivatives.
• Exemplary compounds include divinyl, diallyl, or dimethallyl esters, ethers, amides, or ureas. Specific examples are disclosed in U.S. Pat. No. 5,225,473 (Duan) and U.S. Pat. No. 4,931,282 (Asmus et al.).
• PVP polyvinylpyrrolidone
• a range of crosslinked polyvinylpyrrolidone (PVP) materials have been prepared via covalent crosslinking with diallyl maleate or by radiation crosslinking of linear PVP powders.
• Crosslinked PVP prepared under these techniques can produce colloidal particles which are highly swellable in aqueous solutions and thereby produce viscous solutions.
• the polymers are also nonionic and have excellent compatibility with cationic excipients.
• Anionic swellable polymeric thickeners may also be useful.
• preferred anionic polymers for use with antimicrobial compositions which include carboxylic acid functional enhancers are polymers having sulfonic acid, sulfonate, phosphonic acid, or phosphate groups.
• Associative Polymers can be used to thicken the compositions of the present invention as well. Such polymers thicken as a result of hydrophobic or Van de Waals association of hydrophobic side chains. Such associative polymers can form viscous to gelled aqueous solutions despite their relatively low molecular weights. Polymers that are alcoholic soluble can be modified by the addition of a long chain hydrophobic group.
• a preferred class of such associative polymers are based on nonionic ethylenically unsaturated monomers wherein at least one comonomer has at least 16 carbon atoms.
• cetyl hydroxyethylcellulose available as NATROSOL PLUS from Aqualon, which utilizes an associative mechanism to enhance the viscosity it produces. Grafted side chains of cetyl alkyl groups can associate with neighboring alkyl hydrophobes. These interpolymer associations can dramatically increase the viscosification efficiency of the polymer. Longer chain alklyl, alkenyl, and aralkyl groups may also be suitable.
• Arsitoflex HMB is ammonium acryloyldimethyltaurate/beheneth-25 methacrylate crosspolymer and is available from Clariant Corp.
• compositions of the present invention have a viscosity of at least 500 Centipoise (cps) for ease of application topically. More preferably, compositions of the present invention have a viscosity of at least 1,000 cps, even more preferably at least 10,000 cps, even more preferably at least 20,000 cps, even more preferably at least 50,000 cps, even more preferably at least 75,000 cps, even more preferably at least 100,000 cps, and even more preferably at least 250,000 cps (and even as high as about 500,000 cps, 1,000,000 cps, or more).
• cps Centipoise
• Lower viscosity compositions can be used, however, in certain applications, such as for the treatment of middle ear infection and chronic sinusitis.
• afflictions of the middle ear e.g., otitis media or infection of the middle ear
• compositions of the present invention having a viscosity lower than 1000 cps more readily by administration through the nose and into the Eustachian tubes.
• the antimicrobial compositions may be provided as a formulation suitable for delivery to skin and/or mucosal surfaces, for example.
• suitable formulations can include, but are not limited to, creams, gels, foams, ointments, lotions, balms, waxes, salves, solutions, suspensions, dispersions, water in oil or oil in water emulsions, microemulsions, pastes, powders, oils, lozenges, boluses, and sprays, and the like.
• Spray formulations may include propellents such as those common to the industry including but not limited to dimethyl ether, lower alkanes such as propane and butane, HCFCs, perflouroalkanes, and the like.
• compositions of the present invention can be formulated into various consumer products, such as deodorants, shampoos, shower gels, detergents, household cleaning products, etc.
• Topical antimicrobial treatment regimens include applying a safe and effective amount of the compositions described herein directly to the infected or at-risk skin or mucous membrane; particularly, the nasal nares and passages that are particularly susceptible to microbial contamination.
• Compositions of the present invention can be delivered using a variety of techniques. Typically, the compositions are delivered to the skin and/or mucosal tissue in a manner that allows them to penetrate into the skin and/or mucosal tissue, as opposed to through the tissue into the blood stream. This concentrates the compositions locally at the site in need thereof. This can be accomplished by spraying, dipping, wiping, dropping, pouring, toweling, or the like, onto the area to be treated.
• afflictions of the middle ear may be treated with compositions of the present invention by administration through the nose and into the Eustachian tubes or they can be instilled directly into the middle ear through the tympanic membrane.
• the formulations may traverse the tympanic membrane with the aid of a syringe or do so by diffusion.
• Penetration enhancers may be used to enhance diffusion across the tympanic membrane.
• Various other methods will be well known to one of skill in the art depending on the desired location for contact of the antimicrobial compositions of the present invention.
• compositions of the present invention may be applied to a mucosal surface with the use of a delivery device such as cervical caps, diaphragms and solid matrices such as tampons, cotton sponges, cotton swabs, foam sponges, and suppositories.
• a delivery device such as cervical caps, diaphragms and solid matrices such as tampons, cotton sponges, cotton swabs, foam sponges, and suppositories.
• compositions of the present invention can also be incorporated in (e.g., impregnated into) cloth, sponges, paper products (e.g., paper towels, towelletes, and wipes), tampons, undercast padding, and dental floss, for example.
• an applicator may be used to place the device and/or antimicrobial composition in the proper location, for example, on the mucosal surface of a vagina, nasal cavity, rectum, or the like.
• applicators include, for example, cardboard or plastic tube applicators commonly used for inserting tampons or suppositories.
• compositions of the present invention can be coated onto medical devices that contact skin, mucous membranes, wounds, etc.
• medical devices include catheters such as urinary tract catheters and vascular access catheters.
• the dose and frequency of application will depend on many factors including the condition to be treated, the concentration of antimicrobial lipid and enhancer, the microbe to be killed, etc.
• the compositions will be delivered in dosages of 0.1 gram to 5 grams for most applications.
• Application can be made once, or preferably several times daily for one or more days.
• the composition is applied 1 or 2 times/day for 1-7 days.
• decolonization of the anterior nares may require a dose of 0.25 gram (g) per nare applied 1-3 times per day for 1-5 days.
• Treatment of impetigo may require about 0.5 g/15 cm 2 applied 1-3 times/day for 3-10 days.
• Antimicrobial compositions were challenged with test cultures of Methicillin Resistant Staphyloccus aureus (MRSA) #MS 16266 and Staphylococcus aureus ( S. aureus ), ATCC #25923 (commercially available from American Type Culture Collection, Rockville, Md.), Escherichia coli ( E. coli ), ATCC # 11229, and Pseudomonas aeruginosa ( Pseudomonas ae .), ATCC # 15442.
• MRSA Methicillin Resistant Staphyloccus aureus
• S. aureus Staphylococcus aureus
• ATCC #25923 commercially available from American Type Culture Collection, Rockville, Md.
• Escherichia coli E. coli
• ATCC # 11229 ATCC # 11229
• Pseudomonas aeruginosa Pseudomonas ae .
• TSB Tryptic Soy Broth
• ml 0.3 milliliter (ml) culture suspension was spread on the surface of a Tryptic Soy Agar plate that was incubated at 35° C. for 18-24 hrs.
• Bacterial cells were harvested from the agar plate with a glass L-rod by adding 3 ml of TSB and were transferred into a snap cap 5 ml polypropylene culture tube. The resulting cell suspension was called the working culture.
• a 50 ml centrifuge tube was filled with 10 ml of each ointment antimicrobial composition.
• the tube was placed in a temperature controlled water bath equipped with stirring capability.
• the temperature of the composition was adjusted to 40° C. +/ ⁇ 2° C. where most of the compositions became softened and could be easily mixed. Other compositions may require higher or lower temperatures.
• the temperature should not be increased above about 45° C. at which point the bacteria will perish from temperature effects. It should be confirmed that the temperature did not kill the bacteria in the absence of the antimicrobial composition.
• a 25 ml Erlenmeyer flask containing a magnetic stirring bar was filled with 20.0 ml of a liquid antimicrobial composition.
• the flask was placed in a temperature controlled water bath equipped with stirring capability.
• the magnetic stirrer was turned on and temperature of the composition was adjusted to 23° C. +/ ⁇ 2° C.
• 0.1 ml volume was plated onto a TSA plate and spread with the L-rod producing 10 ⁇ 2 and 10 ⁇ 3 dilutions.
• the plates were incubated at 35° C. ⁇ 2° C. for 48 hrs and colony-forming units (CFU) were counted and recorded. The procedure was repeated using three to five replicate samples of each composition.
• the diluted bacterial suspensions were plated in duplicate.
• Microbial kill rate was reported as a log 10 reduction which was determined by calculating the difference between the log 10 of the initial inoculum count and the log 10 of the inoculum count after exposure to compositions or components of the composition for 2-minute (T 2 ), 5-minute (T 5 ), and 10-minute (T 10 ) intervals.
• sample inoculums were diluted (0.1 ml in 10 ml of the compositions, the initial inoculum were reduced by 0.1 ml/10 ml, which equals 0.010).
• T 2 , T 5 , and T 10 CFU of 3 replicates ⁇ 1/dilution level where the plate count of 3 replicates are at 2 minute, 5 minute, and 10 minute intervals, respectively.
• the average of the replicates was calculated by averaging the log reductions at each time period.
• Antimicrobial Compositions were prepared and while in a well-mixed, liquid state, were poured into individual vials to solidify.
• the zero time (To) vials were refrigerated at 4° C. and the other vials were placed in a LAB LINE Orbital Environmental Incubator and incubated at either 23° C. or 40° C. and 65° C. at 200 RPM.
• Compositions incubated at 65° C. were in the liquid state. These compositions were incubated with and without shaking to see if agitation contributed to loss of GML.
• One vial of each composition was removed after 7 days and after 4 weeks. After they were removed, they were shaken until they solidified and refrigerated at 4° C. until assayed.
• the internal standard which was used for all extractions, contained 0.4 mg/ml monodecyl glycerol (GMC 10 ) from Sigma-Aldrich in chloroform and was prepared and stored in a clean glass bottle which was sealed with a TEFLON lined screw cap. At the time of assay, methanol was mixed with the stock standard in the ratio of 2 parts chloroform to 1 part methanol giving a stock internal standard which was 0.267 mg/ml in GMC 10 .
• GMC 10 monodecyl glycerol
• the stock standard (1.8 mg/ml) was prepared by adding 18 mg of GML from Sigma-Aldrich to a tared 10 ml volumetric flask, recording the exact weight, filling it to the mark with the stock internal standard, and mixing it well.
• the solution was transferred to a clean glass vial, which was sealed with a TEFLON lined screw cap.
• volume of Standard Volume of Internal GML level Standard Standard Standard (mg/ml) 1 Stock 5 5 0.9 2 Standard 1 2 4 0.3 3 Stock 1 8 0.2 4 Standard 3 3 3 0.1
• the dilutions were stored in clean glass vials and sealed with TEFLON lined screw caps.
• test samples and matrices were allowed to reach room temperature before assay. They were mixed well by stirring with clean glass rods. Using graduated pipettes and clean glass vials which held 7-8 ml, the extractions were performed as follows: Triplicate 50 mg samples of each aged composition were added to tared vials and the exact weights recorded. (For samples that were emulsions with a larger droplet size, larger samples were needed to ensure a uniform sample. In those cases, a larger sample size was obtained and processed proportionately.) To these 5.0 ml of internal standard were added. The samples were mixed until they dissolved or were evenly dispersed and then 1.7 ml of 0.4 weight percent potassium chloride solution was added to each.
• the vials were capped, vortexed for 1 minute, and then centrifuged at top speed on a clinical centrifuge (IEC) until 2 clear phases resulted (3-5 minutes).
• the lower phase organic
• the upper phase aqueous
• Pasteur Pipette which had been inserted through the upper phase. It was transferred to a second vial containing a small amount (approximately 200 milligrams (mg)) of sodium sulfate in order to dry the sample. A portion was then transferred to an auto sampler for GC analysis.
• the order of analysis was: Internal Standard blank, standards (lowest to highest), solvent blank, samples (in random order), and calibration checks every 16 injections and at the end (level 2 standard). Each sample and standard was injected once.
• the Gas Chromatography Conditions were: Instrument HP 5890 or 6890 Column 15 meter ZB-5, 0.25 micon ( ⁇ ) film 0.25 mm ID Carrier He, 22 pounds per square inch (psi) constant pressure (6890-constant flow 1 millilters per minute (ml/min)) Injection 2 microliter ( ⁇ l) split 1:60, injector temp 350° C.
• Liner Restek SILTEK deactivated liner with SILTEK deactivated glass wool (Cat. No. 22406-213.5) Program 110° C. initial, 4° C./min to 210° C., 25° C./min to 350° C., hold 5 minutes (min) Detector FID at 350° C.
• the triplicate samples of each time point were prepared and analyzed once.
• the area ratio of GML/internal standard (GMC 10 ) was converted into mg GML/sample using the standard curves, which was then divided by the sample weight (100 mg) and multiplied by 100 to obtain a weight percent of GML in the sample.
• the weight percent from each of the triplicate samples were then averaged and a standard deviation was obtained.
• MSSA Methicillin Susceptible Stapyloccus aureus
• each culture was again centrifuged and the bacterial pellet was divided into two aliquots.
• One aliquot was resuspended in MHB containing fresh antimicrobial compositions at twice the previous concentrations and returned to the incubator for continued exposure.
• the second aliquot was screened for MRSA and MSSA by incubation with 2 mL of MHB containing 4 ⁇ g/mL of mupirocin or 1,200 ⁇ g/mL of Examples 31 (IPA) or 32 (IPA) or 33 (IPA).
• the resistance screens were incubated overnight at 35° C. in room air. After incubation, each screen was subcultured to fresh MHB and incubated for 4 to 6 hours. Minimum inhibitory concentration (MIC) testing was performed on logarithmically growing bacteria recovered from the screen. This procedure was repeated for 8 days. After 8 days of serial exposure, each bacterial pellet was resuspended in bland MHB and incubated overnight.
• the MIC of each antimicrobial composition or mupirocin was determined as the MIC 90 (range) before and daily during serial passage.
• viscosity was measured at 23° C. at ambient pressure using a Brookfield LVDV-I + viscometer equipped with a model D Brookfield heliopath and T spindles B-F.
• the spindle and speed was chosen for each particular sample such that the viscometer was operating in the middle of its range. All samples were allowed to equilibrate at 23° C. for 24 hours prior to measurement.
• the viscosity is taken at the lowest speed possible while staying within 20-80% of the viscometer range and more preferably between 30-70% of the range. In all cases the sample size and container geometry was chosen to ensure that there were no wall effects.
• the viscosity of each sample was taken as the highest relatively stable reading achieved on the first path the spindle traversed using the heliopath adapter.
• HMB acryloyldimethltaurate/ beheneth 25 methacrylate crosspolymer SALCARE Copolymer of acrylamide Ciba Specialty SC92 and Chemicals Corp./ trimethylaminoethylmeth High Point, NC acrylate chloride salt NATROSOL Cetyl hydroxyethyl Hercules, Aqualon PLUS TYPE cellulose Division/Wilmington, DE
• Antimicrobial compositions were prepared using the components shown in Table 1a.
• White petrolatum was heated in a beaker to at least approximately 82° C.
• glycerin and DOSS were heated until the DOSS was dissolved and this solution was allowed to cool to approximately 82° C.
• the contents of the first beaker was mixed with the contents of the second beaker with a mixing propeller. Mixing was continued until the mixture cooled to 71° C. at which point the GML was added and mixing continued as the mixture continued to cool. When the mixture had cooled to about 54° C., the lactic acid was added and mixing continued until the composition was about to congeal.
• Example 1 had good kill against both MRSA (Gram positive) and E. coli (Gram negative) organisms.
• the log reduction was in excess of 3.5 logs after 5 minutes and 5 logs after 10 minutes.
• Elimination of the surfactant from the formulation (Example 2) resulted in a significant reduction in antimicrobial efficacy.
• Elimination of the antimicrobial lipid and enhancer resulted in poor kill rate—less than 3 log reduction after 10 min (Comparative Example A).
• Antimicrobial compositions were prepared as described in Examples 1-2 using the components shown in Table 2a.
• Mandelic acid was ground into a fine powder using a mortar and pestle and added to the glycerin and DOSS and heated to about 88° C. for Examples 3 and 4 or added directly to the hot, molten petrolatum at about 82° C. for Examples 5 and 6.
• TABLE 2a Components (weight percent) Example Mandelic DOSS White No. GML Acid (100%) Glycerin Petrolatum 3 3.00 1.00 1.00 10.00 85.00 4 3.03 0.92 0.00 10.11 85.94 5 3.00 1.00 1.00 0.00 95.00 6 3.00 1.00 0.00 0.00 96.00 7 2.97 0.90 0.00 0.96 95.17
• Example 3 contained a hydrophilic component (glycerin) and surfactant (DOSS) in addition to the antimicrobial lipid (GML) and enhancer (mandelic acid). This sample had the best antimicrobial activity overall, achieving greater than 5.9 log reduction against all three organisms at 10 minutes.
• Example 4 contained no surfactant (no DOSS), which led to a decrease in activity over Example 3.
• Example 5 which contained no hydrophilic component had decreased activity over Example 3 but the effect was not as great as elimination of the surfactant.
• Example 6 containing no hydrophilic component or surfactant showed relatively poor antimicrobial activity. Addition of only 1% hydrophilic component (Example 7) showed an improvement in antimicrobial activity.
• An antimicrobial composition was prepared using the components listed in Table 3a.
• GML, isopropyl isosterate, beeswax and FINSOLV TN were combined in a beaker, heated and stirred with a propeller mixer until a clear solution was obtained. Stirring was continued while cooling the solution to about 48° C. when the lactic acid was added. Stirring and cooling continued until the temperature was 43° C. when the composition was removed from the mixer and poured into the ointment jar.
• TABLE 3a Components (weight percent) Example Lactic White Isopropyl FINSOLV No. GML acid (88%) Beeswax isosterate TN 8 10.00 1.00 20.00 29.00 40.00
• Example 8 was evaluated using the Antimicrobial Kill Rate Test and the results are shown in Table 3b and 3c. TABLE 3b MRSA (log reduction) E. coli (log reduction) Example After 2 After 5 After 10 After 2 After 5 After 10 No. minutes minutes minutes minutes minutes minutes 8 >6.3 >6.3 >6.3 7.3 7.3 7.3 7.3
• Antimicrobial Compositions were prepared as described in Examples 1-2 using the components shown in Table 4a. The surfactants were added like DOSS in Example 1. TABLE 4a Components (weight percent) Example Lactic Surfactant Component No. GML acid Glycerin Type Amt. Type Amt.
• Examples 9, 13, 15, and 16 had exceptional kill rates (>5 logs) after only 2 minutes against both MRSA and E. coli .
• the surfactants in these examples were anionic (sulfate, sulfonate, and phosphate).
• Example 11 also had very a good kill rate; however, the ethoxylation on this surfactant may have contributed to the lower efficacy shown against E. coli at the 2-minute and 5-minute time intervals.
• Example 10 contained DOSS, which had an exceptional kill rate (>6 logs) against both MRSA and E. coli after 10 minutes of exposure.
• Examples 12 and 14 contained zwitterionic and amine oxide surfactants, respectively, and the kill rate, while still good, was not as good as that of the anionic surfactants.
• First isopropylidene glycerol was prepared by adding 100 grams (g) glycerol, 400 ml acetone, 0.65 g p-toluenesulfonic acid, and 50 g of 3A molecular sieves to a 1-liter NALGENE bottle with a cap. Rolling the bottle on a roller for 24 hours mixed the contents of the bottle. Next 0.95 g potassium carbonate (K 2 CO 3 ) was added to the contents. The mixture was filtered, passed through an activated alumina column, concentrated on a rotary evaporator, and distilled using a water aspirator to pull a vacuum (boiling point (bp) approximately 100° C.). The final product was then used to prepare glycerol ether.
• K 2 CO 3 potassium carbonate
• An antimicrobial composition was prepared using the components in Table 5a.
• the white petrolatum was heated to approximately 93° C. and the DOSS and the glyceryl ether were added to it while stirring using a mixing propeller. The mixture was stirred while being held at 93° C. until a clear solution was formed. The mixture was allowed to start cooling with continuous stirring. When the mixture reached approximately 65° C. the glycerin was added and the cooling and stirring continued. When the mixture reached approximately 49° C. the lactic acid was added and cooling and stirring continued until the composition was about to congeal (approximately 38° C.) and then it was poured into an ointment jar.
• TABLE 5a Components (weight percent) 88% C 10 H 23 Example Lactic glycerin 100% White No. Acid ether DOSS Glycerin petrolatum 17 1.13 1.46 1.02 10.07 88.94
• Example 17 were evaluated using the Antimicrobial Kill Rate Test and the results are shown in Table 5b. TABLE 5b MRSA (log reduction) E. coli (log reduction) Example After 2 After 5 After 10 After 2 After 5 After 10 No. minutes minutes minutes minutes minutes minutes minutes minutes 17 3.16 3.70 4.51 4.68 5.88 5.47
• An antimicrobial composition was prepared using the components in Table 6a as described for Examples 1 and 2 but propylene glycol monocaprate was substituted for GML. TABLE 6a Components (weight percent) 88% Propylene Example Lactic glycol 100% White No. Acid monocaprate DOSS Glycerin petrolatum 18 1.12 3.01 1.00 9.92 84.95
• Example 18 were evaluated using the Antimicrobial Kill Rate Test and the results are shown in Table 6b. TABLE 6b MRSA (log reduction) E. coli (log reduction) Example After 2 After 5 After 10 After 2 After 5 After 10 No. minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes minutes 18 6.54 6.54 6.54 5.64 5.88 5.88
• the antimicrobial composition containing propylene glycol monocaprate and an enhancer achieved an exceptional kill rate against MRSA (over 6 log reduction in 2 minutes) as well as an exceptional kill rate against E. coli (over 5.5 log reduction in 2 minutes).
• Antimicrobial compositions were prepared as described for Examples 1-2 using the components in Table 7a. However, hydrophilic components were substituted for the glycerin. TABLE 7a Components (weight percent) Example 88% 100% Hydrophilic component White No. GML Lactic Acid DOSS Type Amt. petrolatum 19 3.02 1.10 0.97 HYDROLITE 5 9.64 85.28 20 3.00 1.13 1.00 PEG 400 9.97 84.90 21 3.01 1.15 1.00 DMI 9.95 84.90 22 3.01 1.12 0.98 NIAX LG650 9.85 85.04 23 3.00 1.13 1.00 DOWANOL TPnB 10.05 84.82 24 1.45 1.13 0.98 Glycerin 9.89 86.55
• Antimicrobial compositions were prepared using the method described for Examples 1-2 and the components in Table 8a.
• the hydrophobic components were heated in a beaker to at least approximately 82° C. instead of the white petrolatum and the hydrophilic components were substituted for the glycerin.
• salicylic acid was substituted for lactic acid.
• TABLE 8a Components (weight percent) 88% Hydrophilic Example Lactic 100% Component Hydrophobic Component No. GML Acid DOSS Type Amt. Type Amt.
• Example 28 was evaluated using the Antimicrobial Kill Rate Test and the results are shown in Table 8b.
• Table 8b MRSA (log reduction)
• E. coli (log reduction) Example After 2 After 5 After 10 After 2 After 5 After 10 No. minutes minutes minutes minutes minutes minutes 28 6.45 >6.45 >6.45 4.62 5.88 >5.88
• Example 28 had an exceptional kill rate against MRSA as well as E. coli .
• the use of the DMI improved the composition's stability over that of Example 25, which tended to split into distinct phases upon standing.
• Antimicrobial Compositions were prepared using the components shown in Table 9a.
• White petrolatum and DOSS were placed in a beaker and heated until a solution was formed at about 104° C. While mixing with an overhead air mixer (Model No. 1AM-NCC-12, Gast, Benton Harbor, Mich.) glycerin and the acid (enhancer) were added. Next the composition was cooled to 66° C. and the GML was added while holding the temperature between 60° C. and 66° C. When all of the components were in solution, it was cooled to about 46° C., removed from the mixer, and poured into an ointment jar. TABLE 9a Components (weight percent) Example Enhancer DOSS White No. GML Type Amt. (100%) Glycerin Petrolatum 31 3.00 88% Lactic 1.00 1.00 10.00 85.00 Acid 32 3.00 Mandelic Acid 1.00 1.00 10.00 84.99 33 3.00 Benzoic Acid 0.50 1.00 10.00 85.49
• Compositions 31-33 were instilled twice a day for two days in the nose of one of the inventors without any indication of irritation. No odor or taste was detected.
• Isopropyl alcohol (IPA) was substituted for petrolatum and glycerin in the compositions from Examples 31 and 32. The amounts of each component are shown in Table 9c. TABLE 9c Components (weight percent) Example Enhancer DOSS Isopropyl No. GML Type Amt. (100%) alcohol 31(IPA) 3.00 88% Lactic Acid 1.00 1.00 95.00 32(IPA) 3.00 Mandelic Acid 1.00 1.00 95.00 33(IPA) 3.00 Benzoic Acid 0.50 1.00 96.50
• compositions were prepared by mixng the ingredients until the components were fully dissolved.
• the IPA modified antimicrobial compositions were tested using the Emergence of Resistance Test. The results are shown at baseline (T 0 ), after eight days (T 8 ) and the ratio of T 0 to T 8 in Table 9d. TABLE 9d MRSA MSSA Example Initial Final Initial Final Number (T 0 ) (T 8 ) T 0 /T 8 (T 0 ) (T 8 ) T 0 /T 8 Mupirocin 0.25 64 256 0.25 128 512 31(IPA) 60 240 4 60 60 1 32(IPA) 120 60 0.5 60 60 1 33(IPA) 60 60 1 60 60 1
• mice (239 described as 25 g to 30 g Hsd:ICR) were challenged intranasally with 10 8 MRSA #561 (a clinical isolate of methicillin resistant staphylococcus obtained from Mayo Clinic, Rochester, Minn.) and arbitrarily assigned to one of five treatment regimens: mupirocin ointment, bland ointment, antimicrobial compositions of Examples 31, 32, and 33.
• the bland ointment consisted of petrolatum (89%), glycerin (10%) and DOSS (1%).
• mice received either no treatment (none) or treatment with 10 ⁇ L per nare of warmed (42° C.) ointment (one of five) to each nare, three times daily for two days Three days after treatment, both anterior nares were swabbed and cultured for MRSA. Colonies appearing to be S. aureus were confirmed with a latex agglutination test. S. aureus was detected in 160 colonization cultures from 239 mice challenged. These mice continued to be studied. The results of the treatments are listed in Table 9e as the number of animals with no MRSA detected after treatment (successful), the percent of the animals treated successfully, the number of animals with MRSA (failure), and the percent of animals whose treatment failed.
• Example 33 was more active than mupirocin and that the antimicrobial compositions of Examples 31 and 32 were as active as mupirocin as measured by eradication of MRSA from the anterior nasopharynx.
• Example 34 was prepared using the components given in Table 10a.
• White petrolatum and GML were heated in a beaker to at least approximately 93° C.
• glycerin, DOSS, and lactic acid were heated until the DOSS was dissolved at approximately 143° C.
• This solution was mixed with a mixing propeller and allowed to cool to approximately 59° C.
• the contents of the second beaker was mixed with the contents of the first beaker with a mixing propeller. Mixing and cooling continued until the composition was about to congeal at approximately 46° C. Just before the composition congealed it was removed from the mixer and poured into ointment jars.
• TABLE 10a Components (weight percent) Example 88% Lactic DOSS White No. GML Acid (100%)
• Glycerin Petrolatum 34 3.00 1.00 1.00 10.00 85.00
• Antimicrobial Compositions were prepared using the components shown in Table 11a.
• PEG 400 and PEG 1450 were melted together in one beaker at about 82° C.
• the glycerin was heated to about 60° C. and the GML was dissolved in the heated glycerin.
• the enhancers and surfactants were added to the first beaker of melted PEGs and mixed with a propeller mixer while keeping the temperature at about 82° C. After the surfactants and enhancers were dissolved in the PEG component, the solution was mixed and cooled to about 63° C. Then the contents of the second beaker, glycerin and GML were added with constant mixing.
• compositions were cooled with continual mixing to just above the congealing point (about 38° C.) and poured into ointment jars.
• TABLE 11a Components (weight percent) Ex. Enhancer Gly- Surfactant PEG PEG No. GML Type Amt. cerin Type Amt. 400 1450 35 3.00 88% Lactic Acid 1.00 20.00 DOSS USP (50%) 2.00 59.00 15.00 36 3.00 Mandelic Acid 1.00 10.00 Pluronic P65 5.00 60.00 21.00 37 3.00 Mandelic Acid 1.00 20.00 DOSS USP (50%) 2.00 59.00 15.00
• the antimicrobial kill rate of these compositions was excellent against all three organisms indicating broad spectrum kill.
• the antimicrobial kill rate was greater than log reduction at 2, 5, and 10 minutes.
• Antimicrobial Compositions were prepared using the components shown in Table 12a.
• the white petrolatum was melted in a beaker on a hot plate with gentle stirring with a propeller mixer while heating from about 88° C. to 93° C.
• the enhancers were dissolved or suspended in the glycerin at about 77° C.
• the DOSS was added to the hot petrolatum (88° C. to 93° C.) in the first beaker and mixed until a clear solution was obtained.
• the contents of the second beaker (glycerin-enhancer mixture) were added to the first beaker and the composition cooled with constant stirring. When the composition had cooled to about 71° C. the GML was added with constant stirring.
• compositions were cooled with continual mixing to just above the congealing point (about 43° C.) and poured into ointment jars.
• TABLE 12a Components (weight percent) White Example Enhancer Gly- DOSS Petrolatum No. GML Type Amt. cerin (100%) USP 38 3.00 Salicylic Acid 0.20 10.00 1.00 85.80 39 3.00 BHA 0.10 10.00 1.00 85.80 EDTA (Na) 2 0.10 40 3.00 BHA 0.10 10.00 0.00 86.69 EDTA (Na) 2 0.10 Methyl paraben 0.10 Propyl paraben 0.01 41 3.00 Benzoic acid 0.50 10.00 1.00 85.50
• compositions of Examples 38-41 were evaluated using the Antimicrobial Kill Rate Test and the results are shown in Table 12b and 12c.
• TABLE 12b MRSA (log reduction) E. coli (log reduction) Example After 2 After 5 After 10 After 2 After 5 After 10 No. minutes minutes minutes minutes minutes minutes minutes 38 3.50 6.26 6.88 3.20 6.74 6.74 39 3.55 4.13 6.45 3.20 3.98 4.13 40 3.33 4.79 5.84 4.66 6.33 6.74 41 4.49 4.54 4.62 5.25 5.32 5.32
• compositions of Examples 31-32, 38-40, and 42-43, and Comparative Examples B-E were evaluated using the Aging Study with GC as described in the Test Protocols and the results are shown in Table 13b, 13c, 13d and 13e.
• Example 31 contains lactic acid and Example 32 contains mandelic acid.
• Table 13b and Table 13c indicate the difference in aging of the two compositions at 23° C. for 9 months and at 40° C. for 4 weeks.
• Table 13d indicate the quantitative results of GML loss after aging at the indicated temperatures for 7 days.
• the compositions that were incubated at 65° C. were in the liquid state so they were phase split and incubated with and without shaking to see if agitation itself contributed further to the GML loss.
• TABLE 13d GML in grams remaining after aging 7 days at: 10° C. 23° C. 40° C. 65° C. 65° Example No.
• Table 13e The results in Table 13e indicate the quantitative results of GML loss after aging at the 40° C. for 28 days.
• the compositions contain a variety of enhancers: lactic acid (Example 31), salicylic acid (Example 38), BHA and EDTA (Example 39), methyl and propyl paraben (Example 40), benzoic acid (Example 42), and glycolic acid (Example 43).
• enhancers lactic acid (Example 31), salicylic acid (Example 38), BHA and EDTA (Example 39), methyl and propyl paraben (Example 40), benzoic acid (Example 42), and glycolic acid (Example 43).
• Examples in Table 13e may all have acceptable aging in that after 4 weeks at 40° C. they had >90% retention of GML. Examples 39, 31, 40, and 42, showed the best
• compositions evaluated are shown in Table 14. TABLE 14 Components (weight percent) Docuate White Compo- Lactic Glycerin sodium petrolatum PEG PEG sition Acid USP USP USP (50%) USP 400 NF 3350 NF W 1.00 10.00 2.00 87.00 0.00 0.00 X 1.00 20.00 2.00 0.00 59.00 18.00 Test Procedure
• a dose was 0.5 ml of Composition W or X applied using a preloaded 1 cm ⁇ 3 plastic syringe.
• the volunteers applied the first dose after viewing a demonstration of the technique.
• the volunteers applied a second and third dose during Day 1.
• One-half of the volunteers (5) were dosed with Composition W and one-half of the volunteers were dosed with Composition X on Day 1 and given a Rhinoscopic Examination of Nares before and after application on Day 1 and after 24 hours on Day 2.
• those volunteers dosed with Composition W on Day 1 received Composition X and those dosed with Composition X on Day received Composition W. They were given a Rhinoscopic Examination of Nares before and after application on Day 8 and after 24 hours on Day 9.
• Composition W was preferred by 10/10 of the volunteers. Five of ten volunteers could not complete all three application of Composition X. They cited stinging, burning and runny noses as primary reasons. Composition X caused more rhinorrhea than Composition W. Volunteers using Composition X felt they could use the ointment for a shorter period of time than with Composition W. Composition W could be felt to remain in the nasal vestibule longer (mean 218 minutes) than Composition X (mean 145 minutes).
• a second panel evaluation was done to determine acceptability of essentially anhydrous ointments based hydrophobic vehicles containing lactic acid or mandelic acid.
• the criteria for the panel were the same as for the first panel.
• the compositions evaluated are given in Table 15. TABLE 15 Components (weight percent) Lactic White Compo- Acid Mandelic DOSS USP Glycerin petrolatum sition USP Acid (50%) USP USP Y 1.00 0.00 2.00 10.00 87.00 Z 0.00 1.00 2.00 10.00 87.00
• test procedure was the same as that used for the first panel except a cotton swab was used to apply the composition rather than a tube.
• Aqueous antimicrobial compositions were prepared using the components listed in Table 16a.
• Water or glycerin (Example 44), GML, mandelic acid, and PLURONIC P-65 were mixed and heated together to 70° C.
• the mixture was sheared on a Silverson Homogenizer for 1 minute to emulsify the components.
• a polymer was added to the warm solution for Examples 45-47.
• the composition was shaken, sealed in glass jars, and the jars were placed on a roller to mix and cool.
• TABLE 16a Components (weight percent) Ex. Mandelic 70% Polymer Water or No. GML acid DOSS Type Amt.
• Examples 44-47 The pH of Examples 44-47 was determined using a pH meter (Denver Instrument, Model 225 from VWR Scientific) and a gel filled, epoxy, combination pH probe (VWR Scientific) and the results are shown in Table 16b.
• the Brookfield viscosity was determined as described above using the Helipath spindles and speed of rotation in rotations per minute (rpm) indicated with the results shown in Table 16b.
• TABLE 16b Example Helipath No. PH Viscosity (cps) spindle Speed (rpm) 44 ND 1 46000 E 1.5 45 2.3 66000 D 1.0 46 2.7 >1.35 Million F 0.5 47 2.6 2000 B 12.0 1 ND means not done.
• the antimicrobial kill rate of these compositions was excellent against all three organisms indicating broad spectrum kill.
• the antimicrobial kill rate was greater than 4 log reduction at 2 minutes and greater than a 5 log reduction at 5 and 10 minutes for all three bacteria. In fact, for many time points complete kill was achieved (as indicated by a “>” sign).

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