Patent Grant
7871649
The present invention relates to compositions comprising combinations of quaternary ammonium compounds and essential oils and/or individual constituents thereof, and methods of using such compositions. It is based, at least in part, on the discovery that such combinations exhibit synergistically enhanced antimicrobial effects.
Essential oils are volatile oils obtained from plant or animal sources and are composed of complex mixtures of several constituents, such as monoterpenes and sesquiterpene hydrocarbons, monoterpene and sesquiterpene alcohols, esters, ethers, aldehydes, ketones, oxides and the like. These essential oils and their isolated constituents are frequently utilized as fragrance and flavor agents, and have been widely used in folk medicine for wound healing properties.
Scientific research has corroborated the beneficial effects of essential oils. Essential oils of eucalyptus have been found to “possess central and peripheral analgesic effects as well as neutrophil-dependent and independent anti-inflammatory activities” (Silva et al., 2003, J. Ethnopharmacol. 89(2-3); 277-283), and similar activity has been observed in essential oils from Lavendula angustifolia Mill. (Hajhashemi et al., 2003, J. Ethnopharmacol. 89(1):67-71). Essential oils have been demonstrated to exhibit antibacterial (Bezic et al., 2003, Phytother. Res. 17(9:1037-1040; Goren et al., 2003, Z. Naturforsch. 58(9-10):687-690; de Abreu Gonzaga et al., 2003, Planta Med. 69(8):773-775; Valero and Salmera, 2003, Int. J. Food Microbiol. 85(1-2): 73-81) and antifungal (Paranagama et al., 2003, Lett. Appl. Microbiol. 37(1):86-90; Shin, 2003, Arch. Pharm. Res. 26(5):389-393; Velluti et al., 2003, Int. J. Food Microbiol. 89:145-154) activities. Virucidal activity of essential oils has also been observed, including direct virucidal effects against Herpes simplex viruses types 1 and 2 (Garcia et al., Phytother. Res. 17(9):1073-1075; Minami et al., 2003, Microbial Immunol. 47(a):681-684; Schuhmacher et al., 2003, Phytomedicine 10:504-510).
Quaternary ammonium compounds (“QAC”) are a group of ammonium salts in which organic radicals have been substituted for all four hydrogens of the original ammonium cation. They have a central nitrogen atom which is joined to four organic radicals and one acid radical. QACs have a tendency to distribute to the interface of two phases (liquid-liquid or solid-liquid) to introduce continuity between the two different phases. QACs are known to have potent antimicrobial activity, capable of disrupting bacterial cell processes. QACs have been used as antiseptics, disinfectants, preservatives, biocides, etc.
Johnson et al. (U.S. Pat. No. 6,319,958 and US20020165130) relates to the use of sesquiterpenoids to promote uptake of exogenous antimicrobial compounds. Similarly, a related article discloses the use of sesquiterpenoids, such as nerolidol, farnesol, bisabolol and apritone, in enhancing bacterial permeability and susceptibility to exogenous antimicrobial compounds, suggesting that sesquiterpenoids have a non-specific and general effect (Brehm-Stecher et al. 2003, Antimicrobial Agents and Chemotherapy, 47(10):3357-3360). In particular, Brehm-Stecher et al. report that nerolidol, farnesol, bisabolol and apritone enhanced the susceptibility of S. aureus to the antibiotics erythromycin, gentamicin, vancomycin, ciproflaxin, clindamycin, and tetracycline. In addition, Brehm-Stecher et al. does not disclose the use of QACs as antimicrobial agents.
There is a continuing desire for an antimicrobial composition that is non-irritating, safe, and effective for repeated use in various professional and non-professional settings.
The present invention relates to antimicrobial compositions comprising combinations of quaternary ammonium compounds and essential oils and/or individual constituents thereof. Such combinations may be comprised in lotions, gels, creams, soaps, etc. for application to skin or mucous membranes. The invention is based, at least in part, on the observation that synergistic antimicrobial effects are achieved with combinations of essential oils and/or individual constituents thereof and low concentrations of quaternary ammonium compounds.
The present invention relates to compositions and methods for their use, wherein the antimicrobial activities of gels, creams, ointments, lotions or soaps is enhanced by the inclusion of synergistic amounts of quaternary ammonium compounds and essential oils and/or one or more individual constituent(s) thereof. The formulations of the instant invention comprise a synergistically effective amount of at least one quaternary ammonium compound and at least one essential oil and/or individual constituent(s) thereof.
The use of the terms, “synergistic” and “synergistically effective,” are used in the present invention to mean a biological effect created from the application of two or more agents to produce a biological effect that is greater than the sum of the biological effects produced by the application of the individual agents.
Examples of quaternary ammonium compounds suitable for use in the instant invention include, but are not limited to, benzalkonium chloride (“BZK”), benzethonium chloride (“BZT”), other benzalkonium or benzethonium halides, including, but not limited to, benzalkonium or benzethonium bromide or fluoride, cetyl pyridinium chloride, alkylamidopropalkonium chloride, behenalkonium chloride, behentrimonium methosulphate, behenamidopropylethyldimonium ethosulphate, stearalkonium chloride, olealkonium chloride, cetrimonium chloride, dequalinium chloride, N-myristyl-N-methyl-morpholinium methyl sulfate, poly[N-[3-(dimethylammonio)propyl]-N′-[3-(ethyleneoxyethelenedimethylammoinio)propyl]urea dichloride], alpha-4-[1-tris(2-hydroxyethyl)ammonium chloride-2-butenyl]-omega-tris(2-hydroxyethyl)ammonium chloride, poly[oxyethylene(dimethyliminio)ethylene(dimethyliminio)-ethylene dichloride].
The concentrations of quaternary ammonium compound may be between about 0.01 and 0.5 percent; preferably the quaternary ammonium compound is benzethonium chloride or benzalkonium chloride at a concentration between 0.05 and 0.3 percent, more preferably between 0.1 and 0.2 percent. These percentages, and other percentages herein, unless specified otherwise, are weight/weight.
Essential oils (“EOs”), as defined herein, are volatile oils obtained from plant or animal sources, or their synthetic equivalents, and are composed of complex mixtures of several constituents as monoterpenes and sesquiterpene hydrocarbons, monoterpene and sesquiterpene alcohols, esters, ethers, aldehydes, ketones, oxides and the like. Examples of EOs include, but are not limited to, bergamot oil, clary sage oil, ylang-ylang oil, neroli oil, sandalwood oil, frankincense oil, ginger oil, peppermint oil, lavender oil, jasmine absolute, geranium oil bourbon, spearmint oil, clove oil, patchouli oil, rosemary oil, rosewood oil, sandalwood oil, tea tree oil, vanilla oil, lemongrass oil, cedarwood oil, balsam oils, tangerine oil, Hinoki oil, Hiba oil, ginko oil, eucalyptus oil, lemon oil, orange oil, and sweet orange oil.
Individual constituents (“ICs”) of essential oils may be isolated from the oil (natural) or entirely or partially synthetic, and include, but are not limited to, 1-citronellol, α-amylcinnamaldehyde, lyral, geraniol, farnesol, hydroxycitronellal, isoeugenol, eugenol, eucalyptol, linalool, citral, thymol, limonene and menthol.
Further examples of ICs include sesquiterpenoid compounds, which may be the active compounds in the essential oils. Sesquiterpenoid compounds, containing 15 carbons, are formed biosynthetically from three 5-carbon isoprene units. Sesquiterpenoid compounds include, but are not limited to, farnesol, nerolidol, bisabolol, apritone, chamazulene, santalol, zingiberol, carotol, and caryophyllen.
Mixtures of one or more EO, one or more IC, and one or more EO as well as one or more IC, are encompassed by the present invention.
The concentrations of EOs and ICs may be between about 0.01 and 10 percent; preferably between 0.05 and 1.0 percent or between 0.05 and 0.5 percent, and more preferably between 0.2 and 0.5 percent. In preferred embodiments, the EO is lemon oil and/or the IC is farnesol.
In certain specific, non-limiting embodiments, the present invention provides for formulations, including but not limited to gels, creams, lotions or ointments further comprising an amount of zinc that inhibits irritation of the skin or mucosa to which the formulation is applied. Zinc may be added counteract the irritating effects of essential oils. The use of zinc in topical compositions is known in the art and disclosed in the following patents: U.S. Pat. Nos. 5,708,023, 5,965,610, 5,985,918 and 6,037,386.
In a preferred embodiment of the invention, low concentrations of two or more water-soluble salts of zinc are used. The term “low concentration” means percentages of free zinc ions (Zn2+) in the gel or cream at less than 0.5% on a weight to weight (w/w) basis. Suitable zinc salts for use in these compositions include zinc acetate (molar solubility in water of 1.64 moles/l), zinc butyrate (molar solubility in water of 0.4 moles/l), zinc citrate (molar solubility in water of <0.1 moles/l), zinc gluconate (molar solubility in water of 0.28 moles/l), zinc glycerate (moderately water soluble), zinc glycolate (moderately water soluble), zinc formate (molar solubility in water of 0.33 moles/l), zinc lactate (molar solubility in water of 0.17 moles/l), zinc picolinate (moderately water soluble), zinc proprionate (molar solubility in water of 1.51 moles/l), zinc salicylate (low water solubility), zinc tartrate (moderately water soluble) and zinc undecylenate (moderately water soluble). In particularly preferred embodiments, the zinc salts comprise a combination of effective amounts of two or more of the following: zinc acetate (0.05-2.0%), zinc citrate (0.05-2.0%), zinc gluconate (0.05-2.0%) and zinc lactate (0.05-2.0%). In preferred embodiments, the zinc salts are 0.2-0.6% zinc gluconate, 0.1-0.3% zinc acetate and 0.1-0.3% zinc lactate. In particularly preferred embodiments, the zinc salts are 0.3% zinc gluconate, 0.1% zinc acetate, and 0.1% zinc lactate, or 0.2% zinc zinc lactate and 0.2% zinc gluconate. Additional compositions that may comprise the synergistic combinations of the invention are described in International Patent Application No. PCT/US03/03896, published on Aug. 14, 2003, as WO03/066001, incorporated by reference herein in its entirety.
The gels, ointments, lotions or creams of the invention may be applied topically to the skin or to the various mucous membranes of the body, including but not limited to those of the oral, nasal, vaginal or rectal cavities.
In preferred embodiments, the gel, lotion, ointment or cream may comprise a mixture of water, a gelling agent, a thickening agent, a hydrophilic or hydrophobic polymer, an emulsifying agent, an emollient, and/or alcohol, such as ethanol. In preferred embodiments, the presently claimed compositions comprise alcohol present at 10-90% w/w, water present at 15-70% w/w, thickeners and/or gelling agents present at 0.05-3.0% w/w, and emollients present at 0.1-3.0% w/w.
In preferred embodiments, if a thickener is present, it is not a polyacrylic acid-based thickener, such as but not limited to, carbomer, carbopol, or ultrez, as polyacrylic acid-based thickeners have been found to be incompatible with quaternary ammonium compounds. Without being bound by any particular theory, it is believed that anionic groups of such thickeners may interact with cationic groups of the quaternary ammonium compound. Preferably, if a gelling agent is used, it is not an anionic agent, but rather a non-ionic or cationic agent.
The compositions of the invention may optionally further include one or more additional antimicrobial agent such as, but not limited to, antiviral, antibacterial, or antifungal substances. Antimicrobial agents also include substances possessing any combination of virucidal or virustatic, bacteriocidal or bacteriostatic, or fingicidal or fungistatic properties. Antimicrobial agents are well known to those of ordinary skill in the art. Examples of antimicrobial agents include, but are not limited to, iodophors, iodine, benzoic acid, dehydroacetic acid, propionic acid, sorbic acid, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, cetrimide, chlorhexidine (free base and/or salts), other biguanides, such as polyhexamethyl biguanide (PHMB) and chlorohexidine gluconate (CHG), chloroeresol, chlorxylenol, benzyl alcohol, bronopol, chlorbutanol, ethanol, phenoxyethanol, phenylethyl alcohol, 2,4-dichlorobenzyl alcohol, thiomersal, clindamycin, erythromycin, benzoyl peroxide, mupirocin, bacitracin, polymyxin B, neomycin, triclosan, parachlorometaxylene, foscarnet, miconazole, fluconazole, itriconazole, ketoconazole, and pharmaceutically acceptable salts thereof. These and further examples of antimicrobial agents useful in this invention can be found in such references as Goodman and Gilman's The Pharmacological Basis of Therapeutics (Goodman Gilman A, Rall T W, Nies A S, Taylor P, ed. (Pergamon Press; Elmsford, N.Y.: 1990)), the contents of which are hereby incorporated by reference.
In an embodiment, the compositions of the invention comprises a biguanide compound selected from the group consisting of chlorohexidine gluconate (CHG) and polyhexarnethyl biguanide (PHMB). Preferably, the biguande compound is present at a concentration of between 0.1 to 2.0% w/w.
Pharmaceutically acceptable chlorhexidine salts are well known to those of ordinary skill in the art and include, but are not limited to, chlorhexidine palmitate, chlorhexidine diphosphanilate, chlorhexidine digluconate (“CHG”), chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulphate, chlorhexidine sulphite, chlorhexidine thiosulphate, chlorhexidine di-acid phosphate, chlorhexidine difluorophosphate, chlorhexidine diformate, chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine di-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate, chlorhexidine succinate, chlorhexidine malate, chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate, chlorhexidine dilactate, chlorhexidine di-α-hydroxyisobutyrate, chlorhexidine diglucoheptonate, chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate, chlorhexidine di-2-hydroxynapthoate, and chlorhexidine embonate.
In formulating compositions of this invention, it is contemplated that the formulations may further comprise ingredients which, while not having the activity of the above-named ingredients, will aid in the formulation and use of the composition as a whole. Examples of such ingredients are well-known to those of ordinary skill in the art of producing formulations for biological purposes. Examples of these ingredients include such substances as binders, emollients, preservatives (such as methyl paraben), lubricants, colorants, perfumes, and the like. Accordingly, when the surface contemplated is skin, the composition of this invention may contain ingredients which are added to known lotions or medicaments, which are physiologically acceptable to skin and which do not contain ingredients which will reverse or retard the action of the irritant-inactivating agent.
In certain non-limiting embodiments of the invention, the composition may be added to pre-existing formulations provided that the ingredients in those formulations do not prevent or retard the activity of the claimed composition. In a preferred embodiment, the claimed composition can be added to creams, ointments, gels or lotions which are commercially available. Examples of commercially available lubricants include, but are not limited to, those lubricants sold under the tradenames “KY JELLY,” “ASTROGLIDE,” and “PREVACARE.” Examples of commercially available lotions include, but are not limited to, those lotions sold under the tradenames “SOFT-SENSE,” “LOTION SOFT,” “CUREL,” and “KERI”. SOFT-SENSE (Johnson & Son, Inc., Racine, Wis.) is known to contain purified water, glycerin USP, distearyldimonium chloride, petrolatum USP, isopropyl palmitate, 1-hexadecanol, tocopheryl acetate (vitamin E USP), dimethicone, titanium dioxide USP, methyl paraben, propyl paraben, sodium chloride, and fragrance. LOTION SOFT (Calgon Vestal, St. Louise, Mo.) is a nonionic moisturizing lotion which is known to contain mucopolysaccharide. CUREL (Bausch & Lomb Incorporated, Rochester, N.Y.) is known to contain deionized water, glycerin, quaternium-5, petrolatum, isopropyl palmitate, 1-hexadecanol, dimethicone, sodium chloride, fragrance, methyl paraben, and propyl paraben.
The claimed compositions may be used in anti-perspirants, aftershave lotions, hydroalcoholic skin disinfectants, and therapeutic creams, etc.
Certain preferred embodiments of the invention comprise, for example but not by way of limitation, one or more of the following: alcohol (10-90% w/w), which could include one or more of ethanol, n-propanol and iso-propanol; one or more zinc compound in an anti-irritant amount; one or more polymeric quatemary ammonium salts of hydroxyethyl cellulose reacted with trimethyl ammonium substituted epoxide (Polyquatemium), such as U-care polymer such as Ucare JR125, JR 400, JR 30M, LR 400, LR30M, or Ucare polymer LK; hydroxypropyl methyl cellulose such as the Methocel A,E,K, and 40 series products as Methocell K4MS, Methocel K100, Methocell 40-202, Methocel K15MS and others; one or more quaternary ammonium compound such as BZK or BZT; cetyltrimethyl ammonium chloride (“CTAC”); cetyl trimethyl ammonium bromide (“CTAB”); olealkonium chloride; stearalkonium chloride; Incroquat BA 85 (babassuamidopropalkonium chloride); dibehenyldimonium methosulfate; IncroquatBES-35 S (Behenamidopropylethyldimonium Ethosulfate and stearyl alcohol); Incroquat B-65C (Behenalkonium chloride and cetyl alcohol); Incroquat Behenyl TMS (Behentrimonium methosulfate and cetearyl alcohol); and one or more emollient, such as Procetyl 10 PPG-10 cetyl ether, Procetyl 50 PPG-50 cetyl ether, Promyristyl PM-3 PPG-3Myristyl ether, PPG-3 benzyl ether myristate (Crodamol STS of Croda), PEG 20 Almond Glycerides, Probutyl DB-10, Glucam P20, Glucam E-10, Glucam P-10, Glucam E-20, Glucam P-20 distearate, glycerin, propylene glycol, cetyl acetate and acetylated lanolin alcohol (Acetulan), hydroxylated milk glycerides (Cremerol HMG); a silicone fluid such as Dow Corning Silicone Fluid 245, 244, 246, 344, 345, 556; an essential oil such as lemon oil, citronella oil, sandalwood oil, lemongrass oil, patchouli oil, clove oil, thyme oil, geranium oil, basil oil; an individual constituent of an essential oil, such as farnesol, citronellol, linalool, eugenol, citral, thymol, eucalyptol, menthol; and a biguanide such as chlorhexidine gluconate or polyhexamethyl biguanide.
The invention provides for methods of using the foregoing compositions to achieve an antimicrobial effect comprising applying an effective amount of the composition to the surface. An antimicrobial effect significantly diminishes the risk of infection or progression of existing infection by one or more pathogenic infectious agent. The risk of infection need not be reduced to zero, but preferably is reduced by at least 10, 20, 30, 40, 50, 60, 70, 80, or 90 percent. Examples of infectious agents against which protection may be afforded include, but are not limited to, Staphylococcus species such as Staphylococcus aureus and Staphylococcus epidermidis, Streptococcus species such as Streptococcus pneumoniae, Enterococcus species, Salmonella species such as Salmonella typh, Escherichia species such as Escherichia coli, Vibrio species, Neisseria species, such as Neisseria meningitidis and Neisseria gonnorhoea, Human Immunodeficiency Virus (HIV), Human Papilloma Virus (HPV), Herpes Simplex Virus (HSV), Chlamydia trachomatis, Trichomonas vaginalis, and Candida albicans.
In an embodiment of the invention, the compositions of the present invention do not contain antibiotics, including, but are not limited to, tetracycline, ampicillin, rifampin, vancomycin, amphotericin B, nystatin, and bacitracin.
The following are specific, non-limiting examples of formulations of the present invention with and without zinc salts.
(M) Alcohol Surgical Hand Prep Containing Zinc Gel
The following formulation is advantageously used by persons who wear latex gloves, but who have a latex allergy.
Topical formulations containing zinc salts as anti-irritants were prepared in the presence and absence of EO and IC and in the presence and absence of antimicrobial compounds, such as benzalkonium chloride (BZK), chlorhexidine gluconate (CHG), zinc pyrithione (ZP) and triclosan (TC). The following EO and IC were evaluated: lemon oil as a representative essential oil, farnesol and linalool as representative terpene alcohols, and citral as a representative aldehyde. The resulting formulations then were evaluated for their antimicrobial activity.
6.1.1. Method
Preparation of Alcohol Based Zinc Gel
An alcohol based gel was prepared as follows, and the antimicrobials, EOs and/or ICs were added to this base:
Evaluation of Rapid Antimicrobial Activity in Presence of Serum
To determine the efficacy of the antimicrobial composition on the skin, which may be contaminated with blood or other proteinaceous fluids containing bacteria, the antimicrobial activity was evaluated in the presence of serum as follows. Briefly, 0.5 ml of 108 CFU of S. aureus/ml was added to 0.5 ml of bovine adult serum in a sterile culture tube and mixed. 0.5 ml of the test formulation was added to each tube and vortexed. After 15 seconds, it was further diluted 1:100 with drug inactivating media (LTSB) and 0.5 ml was plated on a TSA plate. The plates were incubated at 37° C. for 24 hours and the colony count per ml of culture was determined.
6.1.2. Results
It was observed that farnesol, linanool, citral and lemon oil showed synergistic antimicrobial effects when combined with BZK. No such synergism was observed when farnesol was combined with other antimicrobial compounds, CHG, ZP or TC. See Table 1 below.
It can be seen from Table 1 that, among the antimicrobial compounds used, only the quaternary ammonium compound, benzalkonium chloride, exhibited significant synergistic activity in combination with EOs and ICs.
The present example shows the antimicrobial activity of compositions comprising a quaternary ammonium compound, benzethonium chloride (BZT) and farnesol in the presence and absence of zinc salts. The antimicrobial activity was evaluated as described in Example 1.
Famesol and BZT were incorporated into Base #1 (containing zinc salts) and Base #2 (not containing zinc salts) shown below in proportions shown in Table 2.
These results demonstrate the synergistic antimicrobial effects of BZT and farnesol, which occur both in the presence or absence of zinc salts.
The antimicrobial effects of varying proportions of farnesol and quaternary ammonium compounds, incorporated into Base #2, were evaluated using the same method described in Example 1. The results are shown in Table 3.
These results demonstrate that both quaternary ammonium compounds, BZK and BZT, exhibit synergistic antimicrobial activity when used in combination with farnesol on S. aureus in a rapid serum-based assay.
The antimicrobial effects of various EO and IC, in the presence or absence of quaternary ammonium compounds, BZK and BZT, incorporated into Base #2, were evaluated using the same assay described in Example 1. The amounts of various agents used are presented in Table 4. In addition to S. aureus, the rapid assay was also performed with E. coli. The results are shown in Table 4.
S. aureus
E. coli
These results demonstrate that various essential oils, when used in combination with quaternary ammonium compounds, exhibit rapid synergistic antimicrobial activity on S. aureus in a rapid serum-based assay. In particular, patchouli oil, basil oil, eucalyptus oil, thyme oil, clove oil, geranium oil, and citronella oil show pronounced antimicrobial effects.
The effect of the addition of various biguanide antimicrobial compounds to combinations of farnesol and quaternary ammonium compound, incorporated into Base #2 was tested using the assay described in Example 1. The results are shown in Table 5.
S. aureus
E. coli
This example demonstrates the antimicrobial activity of gels comprising farnesol in combination with various antimicrobial agents. The concentrations of the antimicrobial agents were selected in keeping with the permissible levels of these ingredients in leave-on skin care formulations. The antimicrobial activity was assayed using the method described in Example 1 using Gel Base #1. The data has been presented in Table 6.
aThe colony count of the Control Base experiment was 3.4 × 107 cfu/ml.
bFor Control, the same Gel Base as used for the Gels shown in Table 6, but without any antimicrobial agents.
The results show that farnesol's ability to enhance the activity of the antimicrobial agents ranges from compound to compound. Farnesol shows synergy with the quaternary ammonium compounds, benzalkonium chloride (BZT) and benzethonium chloride (BZK). Among biguanide antimicrobial compounds, it enhances the activity of polyhexamethylene biguanide hydrochloride (PHMB), but not that of chlorhexidine gluconate (CHG). Farnesol also does not show any synergy with triclosan, nor does it enhance triclosan's action. Therefore, the ability of farnesol to show synergy or enhance the action of biocides/preservatives is specific to the antimicrobial agents in question.
A similar study was performed using the same concentration of farnesol above in Table 6 (0.3% w/w, i.e. 1.35 mM per 100 g gel) and the various antimicrobial agents were added to the gel in the same molar concentration (0.06 mM per 100 g of gel). The data has been presented in Table 7 below.
aThe colony count of the Control Base experiment was 6.4 × 107 cfu/ml.
bFor Control, the same Gel Base as used for the Gels shown in Table 7 but without any preservatives/biocides was used.
cSince Triclosan is not effective even at 1.04 mM concentration, experiment was not performed with 0.06 mM concentration.
Similar to the results shown in Table 6, farnesol has a varying effect on enhancement of the antimicrobial activity of the various antimicrobial agents. Farnesol appears to exhibit synergistic antimicrobial activity in combination with BZT, but not with triclosan. PHMB appears to enhance the acitivity of farnesol. The mechanism of farnesol to show synergy or enhance the activity of the antimicrobial agents varies for different compounds, but is the same for the same compound, irrespective of the concentration (whether the compound is taken in % w/w or in molar proportions).
Various references, patents, publications, product descriptions, etc., are cited throughout this specification, the disclosures of which are incorporated herein by reference in their entireties for all purposes.
The present application claims the benefit of U.S. Provisional Application Ser. Nos. 60/488,349, and 60/530,864, filed Jul. 17, 2003, and Dec. 18, 2003, respectively, each of which are incorporated herein by reference in their entireties.
| Number | Name | Date | Kind |
|---|---|---|---|
| 3257276 | Broh-Kahn et al. | Jun 1966 | A |
| 3485915 | Gerstien et al. | Dec 1969 | A |
| 3960745 | Billany et al. | Jun 1976 | A |
| 4243657 | Okumura et al. | Jan 1981 | A |
| 4318907 | Kligman et al. | Mar 1982 | A |
| 4393076 | Noda et al. | Jul 1983 | A |
| 4478853 | Chaussee et al. | Oct 1984 | A |
| 4587266 | Verdicchio | May 1986 | A |
| 4604384 | Smith et al. | Aug 1986 | A |
| 4814334 | Salkin | Mar 1989 | A |
| 4853978 | Stockum | Aug 1989 | A |
| 4868169 | O'Laughlin et al. | Sep 1989 | A |
| 4870108 | Page | Sep 1989 | A |
| 4889844 | Silvetti, Sr. et al. | Dec 1989 | A |
| 4910205 | Kogan et al. | Mar 1990 | A |
| 4919837 | Gluck | Apr 1990 | A |
| 4956170 | Lee et al. | Sep 1990 | A |
| 4963591 | Fourman et al. | Oct 1990 | A |
| 4966754 | Purohit et al. | Oct 1990 | A |
| 5031245 | Milner | Jul 1991 | A |
| 5059416 | Cherukuri et al. | Oct 1991 | A |
| 5073372 | Turner et al. | Dec 1991 | A |
| 5089205 | Huang et al. | Feb 1992 | A |
| 5110809 | Wang et al. | May 1992 | A |
| 5116602 | Robinson et al. | May 1992 | A |
| 5133090 | Modak et al. | Jul 1992 | A |
| 5147648 | Bannert | Sep 1992 | A |
| 5164107 | Khan et al. | Nov 1992 | A |
| 5208031 | Kelly | May 1993 | A |
| 5357636 | Dresdner, Jr. et al. | Oct 1994 | A |
| 5403864 | Bruch et al. | Apr 1995 | A |
| 5447930 | Nayak | Sep 1995 | A |
| 5516510 | Beilfuss et al. | May 1996 | A |
| 5591442 | Diehl et al. | Jan 1997 | A |
| 5599549 | Wivell et al. | Feb 1997 | A |
| 5612324 | Guang Lin et al. | Mar 1997 | A |
| 5624675 | Kelly | Apr 1997 | A |
| 5624962 | Takeuchi et al. | Apr 1997 | A |
| 5648389 | Gans et al. | Jul 1997 | A |
| 5658575 | Ribier et al. | Aug 1997 | A |
| 5705532 | Modak et al. | Jan 1998 | A |
| 5708023 | Modak et al. | Jan 1998 | A |
| 5736574 | Burnier et al. | Apr 1998 | A |
| 5750122 | Evans et al. | May 1998 | A |
| 5753270 | Beauchamp et al. | May 1998 | A |
| 5776430 | Osborne et al. | Jul 1998 | A |
| 5804203 | Hahn et al. | Sep 1998 | A |
| 5830488 | Suzuki et al. | Nov 1998 | A |
| 5885562 | Lowry et al. | Mar 1999 | A |
| 5888562 | Hansen et al. | Mar 1999 | A |
| 5902572 | Luebbe et al. | May 1999 | A |
| 5906808 | Osborne et al. | May 1999 | A |
| 5951993 | Scholz et al. | Sep 1999 | A |
| 5965137 | Petrus | Oct 1999 | A |
| 5965610 | Modak et al. | Oct 1999 | A |
| 5980477 | Kelly | Nov 1999 | A |
| 5980925 | Jampani et al. | Nov 1999 | A |
| 5985918 | Modak et al. | Nov 1999 | A |
| 5985931 | Modak et al. | Nov 1999 | A |
| 6022551 | Jampani et al. | Feb 2000 | A |
| 6037386 | Modak et al. | Mar 2000 | A |
| 6040347 | Cupferman et al. | Mar 2000 | A |
| 6045817 | Ananthapadmanabhan et al. | Apr 2000 | A |
| 6107261 | Taylor et al. | Aug 2000 | A |
| 6110908 | Guthery | Aug 2000 | A |
| 6136771 | Taylor et al. | Oct 2000 | A |
| 6183766 | Sine et al. | Feb 2001 | B1 |
| 6187327 | Stack | Feb 2001 | B1 |
| 6204230 | Taylor et al. | Mar 2001 | B1 |
| 6211243 | Johnson | Apr 2001 | B1 |
| 6248343 | Jampani et al. | Jun 2001 | B1 |
| 6287577 | Beerse | Sep 2001 | B1 |
| 6287583 | Warren et al. | Sep 2001 | B1 |
| 6294186 | Beerse et al. | Sep 2001 | B1 |
| 6319958 | Johnson et al. | Nov 2001 | B1 |
| 6321750 | Kelly | Nov 2001 | B1 |
| 6323171 | Fonsny et al. | Nov 2001 | B1 |
| 6344218 | Dodd | Feb 2002 | B1 |
| 6352701 | Scholz et al. | Mar 2002 | B1 |
| 6376522 | Holzl et al. | Apr 2002 | B1 |
| 6387357 | Chopra et al. | May 2002 | B1 |
| 6403067 | Schamper et al. | Jun 2002 | B1 |
| 6403071 | Scavone et al. | Jun 2002 | B1 |
| 6414032 | Johnson | Jul 2002 | B1 |
| 6420431 | Johnson | Jul 2002 | B1 |
| 6426062 | Chopra et al. | Jul 2002 | B1 |
| 6485716 | Fei et al. | Nov 2002 | B1 |
| 6511657 | Avendano et al. | Jan 2003 | B2 |
| 6582711 | Asmus et al. | Jun 2003 | B1 |
| 6613312 | Rizvi et al. | Sep 2003 | B2 |
| 6682749 | Potechin et al. | Jan 2004 | B1 |
| 6723689 | Hoang et al. | Apr 2004 | B1 |
| 6846846 | Modak et al. | Jan 2005 | B2 |
| 7435429 | Modak et al. | Oct 2008 | B2 |
| 7563461 | Modak et al. | Jul 2009 | B2 |
| 20020022660 | Jampani et al. | Feb 2002 | A1 |
| 20020098159 | Wei et al. | Jul 2002 | A1 |
| 20020165130 | Johnson et al. | Nov 2002 | A1 |
| 20030134780 | Patt | Jul 2003 | A1 |
| 20030152644 | Modak et al. | Aug 2003 | A1 |
| 20030157138 | Eini et al. | Aug 2003 | A1 |
| 20030211066 | Scholz | Nov 2003 | A1 |
| 20040102429 | Modak et al. | May 2004 | A1 |
| 20040208908 | Modak et al. | Oct 2004 | A1 |
| 20040253275 | Eini et al. | Dec 2004 | A1 |
| 20050019431 | Modak et al. | Jan 2005 | A1 |
| 20050048139 | Modak et al. | Mar 2005 | A1 |
| 20050238602 | Modak et al. | Oct 2005 | A1 |
| 20050281762 | Modak et al. | Dec 2005 | A1 |
| 20060141017 | King et al. | Jun 2006 | A1 |
| Number | Date | Country |
|---|---|---|
| 4140474 | Jun 1993 | DE |
| 4240674 | Mar 1994 | DE |
| 195 23 320 | Jan 1997 | DE |
| 19523320 | Jan 1997 | DE |
| 0041448 | Dec 1981 | EP |
| 304802 | Mar 1989 | EP |
| 402078 | Dec 1990 | EP |
| 0521455 | Jan 1993 | EP |
| 0604848 | Jul 1994 | EP |
| 0 674 896 | Oct 1995 | EP |
| 0674896 | Oct 1995 | EP |
| 0694310 | Jan 1996 | EP |
| 0313302 | Apr 1998 | EP |
| 1 001 012 | May 2000 | EP |
| 1001012 | May 2000 | EP |
| 2729050 | Jul 1996 | FR |
| 10328284 | Dec 1998 | JP |
| 2166309 | May 2001 | RU |
| 833240 | May 1981 | SU |
| WO8400111 | Jan 1984 | WO |
| WO8704350 | Jul 1987 | WO |
| WO 8800795 | Feb 1988 | WO |
| WO8800795 | Feb 1988 | WO |
| WO8803799 | Jun 1988 | WO |
| WO8905645 | Jun 1989 | WO |
| WO9307903 | Apr 1993 | WO |
| WO9318745 | Sep 1993 | WO |
| WO9318852 | Sep 1993 | WO |
| WO9415461 | Jul 1994 | WO |
| WO 9418939 | Sep 1994 | WO |
| WO9526134 | Oct 1995 | WO |
| WO 9824426 | Jun 1998 | WO |
| WO9824426 | Jun 1998 | WO |
| WO 9851275 | Nov 1998 | WO |
| WO9903463 | Jan 1999 | WO |
| WO9938505 | May 1999 | WO |
| WO9938505 | Aug 1999 | WO |
| WO9938505 | Aug 1999 | WO |
| WO 9951192 | Oct 1999 | WO |
| WO 9960852 | Dec 1999 | WO |
| WO9960852 | Dec 1999 | WO |
| WO9963816 | Dec 1999 | WO |
| WO0037042 | Jun 2000 | WO |
| WO 0141573 | Jun 2001 | WO |
| WO0141573 | Jun 2001 | WO |
| WO03003896 | Jan 2003 | WO |
| WO 03034994 | May 2003 | WO |
| WO03034994 | May 2003 | WO |
| WO 03066001 | Aug 2003 | WO |
| WO03066001 | Aug 2003 | WO |
| WO 03083028 | Oct 2003 | WO |
| WO03083028 | Oct 2003 | WO |
| WO2004014416 | Feb 2004 | WO |
| WO2006099359 | Sep 2006 | WO |
| WO2007069214 | Jun 2007 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20050019431 A1 | Jan 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60488349 | Jul 2003 | US | |
| 60530864 | Dec 2003 | US |
