us United States cz) Patent Application Publication co) Pub. No.: US 2008/0194518 Al oy 06) on MOOKERSEE et al. ANTIMICROBIAL COMPOSITIONS, Inventors: Pradip MOOKERIEE Flemington, NJ (US): Shira Kramer, Timonium, MD (US) Alexander Josowity, Balitsmore. MD (US): April Zambeli-Wel Hampstead, MD (US) Correspondence Address: MILES & STOCKBRIDGE PC 1751 PINNACLE DRIVE, SUITE 500 MCLEAN, Va 22102-3833 (US) Appl.No: 111964153 Filed: Dee. 26, 2007 Related Us Application Data Continuation-in-part of application No. 11/644,900, filed on Dee. 26, 2006, Provisional aplication No, 60V753,175, fled on Dee 23, 2008, Publication Classification "Cl. AGIK 311 (2006.01) AGIK 31/722 (2005.01) 'US 2008019451841 (43) Pub. Date: Aug. 14, 2008 ABIK 31/724 200501) A6IK 31/70 (2006.01), AGIK 31/194 (200501), A6IP 31/04 (2006.01), 401P 1/100 (200501), 61K 31/18 (2006.01), AGIK 31705 (200501), AGIK 31/66 (2006.01) AGIK 31/13 (2006.01), (32) US.CL 514/85; 514/161; 514/579; $14158: 514/762: 514/108; 514/23; 514731; 514/57: S14i642 on ABSTRACT An antimicrobial composition, inching a synergstie com bination of three or more agen as anaetve ingredient. Each of the three or more potentiating agents canbe selected from the following types of compounds: sequestering agents, car bohydates and carbohydrate derivatives, terpenesterpe- oid, amines und amine derivatives, plant-derived oils, ste fonates, phenols, fatty acids, dibenzofuran derivatives, ‘organo isothiocyanates, quaternary ammonium compounds peroxides and peroxide donors, and macrolide polyenes. At Ieasttwo ofthe three or more potentiating agents are natof the same type of compound. The antimicrobial composition can |e strong antimicrobial efficacy in contro of mieroorgan isms having resistance to curently used antimicrobialsUS 2008/0194518 AI ANTIMICROBLAL COMPOSITIONS, (CROSS REFERENCE [0001] This application claims the benefit of U.S. Provi- sional Application No. 60°753,175, fled Dee. 23, 2008, and US. application Ser. No, 11/644.900 filed Des, 26, 2006 the ‘entire contents ofeach being hereby incorporated by refer ‘ence ints respective entirety FIELD OF THE INVENTION 10002} This invention relates to antimicrobial composi BACKGROUND [0003] Pathogenic microorganisms, inciting, for ‘example, bacteria, vinwses, and Fungi, are responsible For 3 host of human diseases, ranging from mace minor ailments, suchas upper and lower respiratory trict infections, to poten tally fatal infections, such as Tstriosis 10008] During the lst 100 years. major progress has beea made in combating diseases caused by pathogenic microor- ‘ganisms with the development of copious pharmaceutical and rnon-pharmaceutical agents to be used in treatments. For ‘example, in pharmacy. an antibiotic agent can he used to treat bacterial infections within hnimans, whereas 2 chemical- based apeat ean be used for external treataent (eg.0n hard surface) to prevent contamination and transmission humans, as in the ease of Listeria in ready-to-eat meat and poultry processing plants. 0005) » While agents havebeen developed tha are generally ‘effective against various pathogens, there is increasing evi ‘dence that theuse ofsueh agents has eertain imitations Which ‘warrant concer. Specifically, cen stain of pathogenic microorganisms have become inereasingly resistant to one oF ‘more antimicrobials, thereby rendering the standard courses ‘ftreatment ineffective. Accordingly, higher doses of ant ‘erobial treatments ean be required 10 achieve eficacy, which ‘can result in undesirable side eects and toxieity, both human, and environmental. In addition, many antimicrobial te ‘ments ate not designed to combat bio‘ilm, which is a major ‘contributor to antimicrobial resistance development, both biologically (in vivo) and environmentally BRIEF DESCRIPTION OF THE TABLES. 10006] TABLE 1 provides example proposed embod {0007} TABLE 2 provides example synergistic eombin- tions—MIC data against MRSA [0008] "TABLE. 3 provides example synergistic combina- tions MIC data against E.coli [0009] TABLE 4 provides further synergy dats [0010] TABLE 5 provides comparative data for selected ‘examples. SUMMARY OP THE INVENTION [0011] _Inanaspect, the invention features an antimicrobial ‘composition. The antimicrobial composition inchudes a syn- ‘ergistic combination of three or more agents, sich agents ean be antimicrobial potentiating agents or can be antimicrobial ‘agents. Fach of the three or more agents is independeatly sclecte from varying compounds, The agent can be selected from the following, proups: sequester 5 earbohy- Aug. 14, 2008 rates and carbohydrate derivatives, terpenesterpenoids, amines and amine derivatives, plant-derived oil, sulfonates, phenols, fay acids, dibenzofuran derivatives, organo ‘sothioeyanates, qutemary ammonium compounds, perox- ‘des and peroxide donors, and macrolide polyenes. At least ‘oof the three or more agents are not fem the same group. [0012] In another aspect, amine andl amine derivatives can be further classified as amines, amine oxides, peptides, alka- Joids, and dyes that have an amine funetional g20up. [0013] tn another aspect, carbohydrates and carbohydet ‘erivatives canbe lune classified as earbolydrates and fa {acid polyol esters [0014] In another aspect, the invention features a method for treating « microbial infection, The method includes administering the presenta active ingredient. Proposed include butane not limited t parenteral, oral, sublingual, transdermal, topical, intranasal, aerosol intraocular inratr heal, ntrarectal, vaginal, gene gun, dermal patch, eye drop, far drop and moxthvash, [0015] In another aspect, the invention features a method Tor producing a phannaceutical composition, The method inclides mixing the present antimicrobial composition with a phamaceutically acceptable excipient [0016] Inanother aspect, the invention Features method of treating wounds to prevent and treat infections. The method includes administering the present antimicrobial composition ‘san active ingredient alone or in combination with a ant biotic [0017] In snother aspect, the invention Features method of treating oral infections. The method ineludes administering the present antimicrobial composition as an active ingredient lone or in combination with an antibiotic [0018] In another aspect, the invention features & method Tor treating microorganism-contaminated surface, The ‘method includes applying tothe surface the present anti crobial composition, [0019] Inanother aspet, the invention features method of sterilizing medical devices and equipment. The method includes applying the present antimicrobial composition to the device dr equipment. [0020] Inanother aspect, the invention feauresa method of preserving substances including but not limited to food and beverage producis, cosmetics, personal care products, house- hole prdiuets, paints and wood, The method includes aémin- istering the present antimicrobial composition as an active ingredient. [0021] Inanother aspect, te invention featuresa method of Tormulating a nnteceutieal or cosmeceutical, The method includes administering the present antimicrobial composition as an active ingredient slone or in combination with a nutt- ‘ceutical or eosmeceutical, [0022] Inanother aspect, the invention featuresa method of ‘preventing the formation of bacterial biofilms and provides a ‘method of treating bacterial boflims on surfaces as wel ia the human body: The method includes administering the present antimicrobial composition as an active ingredient Alone or in combination with an antimicrobial or antibiotic. [0023] In another aspect, the invention Ferures amethodot {impregnating materials with a bactericidal and bacteriostatic ingredient, The method includes impregnating surfaces with the present antimicrobial composition [0024] One or more ofthe following fetures can also be includedUS 2008/0194518 AI 10025] The antimicrobial composition can include, as a active ingredient, an antibacterial agent, an antifungal agent ‘or an antiviral agent. The antimicrobial eomposition ean jnclude a pharmaceutially aooeplable excipient [0026] | Microbial infections wo he treated hy the antmicro- bial composition can include bacterial infections caused by ‘drug-resistant bacteria, Likewise, microorganisms of the ‘icroorganisi-conlaminated surfaces ta he treated by the antimicrobial composition ean ineude drugeresistantmicro- ‘organisms, 10027] "Embodiments ofthe invention can baveone or more ‘of te following advantages, 0028] The antimierobial_ compositions of the present Jnventioncanbavestrong antimicrobial elicay i thecontrol ‘of microorganisms having resistance to curently used anti microbial, 10029] Inaccordance withthe present invention, an anti ‘robial potentiating agent need dot be aa antimicrobial agent itself, and ean synergistically boost the efficacy of other ‘agents in the antimicrobial composition by, Tor example, impairing nother fanetions) in wcell that isessentil for cell viability. Such potentiating agents ean include compounds that individually have shown poor antimicrobial activity in screening ess. The antimicrobial compositions can emplay (@) potentiating agents alone as active antimicrobial com pounds, (i) @ potentiating agent(s) with an antimicrobial ‘compounds)toatively revere the resistance of microorgan- jms to the antimicrobial compounds) and make the anti ‘robin! compotind(s) effetive, or (i) a potentiating agents) with an antimicrobial compouils) as an effective combina tion against non-resistant microorganisms 10030] Using the compositions of the present invention, @ ‘microorganism can be tested in the absence of @ known ‘antimicrobial agent, using an antimicrobial agent in lower ‘concentrations, or using an antimicrobial agent which is not ‘elfective when used inthe absence ofthe potentiating agent (s). Thus, methods of treatment using the aatisierobial com- positions can be useful as substitutes for treatments using aa ‘limicrobial agent alone at high dosage levels (which ean, ‘cause undesirable side effets), or as treatments for whieh there isalack ofa clinically effective animicrobil agent. The methods of treatment can be especially useful for treatments ‘involving microorganisms that are susceptible to particular antimicrobial agents asa way to reduce the dossge of those particular gents. This ean duce te risk of side elects, and 1 can also reduce the selection effect for highly resistant riicroorganisis resulting from consistent high level use of @ particular antimicrobial agent [0031] Further aspects, features, and advantages. will become apparent from the following. DESCRIPTION OF AN EMBODIMENT 10032] | Theterm “antimicrobial asused herein efersto the ability of an agent or composition to beneficially coateol oF Kill pathogen, spoilage, or oluerwise harmful microongan- jams, including, but no Fimited to, bacteria fungi, viruses, protezoa, yeasts, mold, and mildew: 10033] The term “potentiating agent” as used herein refers ‘o any compound that ean enhance the eficaey of an ant ‘robial composition as a whole by iaterating with mieroor- anisms ina way that fciitatesorenanees the antimerobial ‘characteristics ofthe composition 10034) _Theterm “active ingredient” as use herein refers to the combination of potentiating agents and, optionally, an Aug. 14, 2008 rob agents that are responsible forthe antimicrobial riclerstics of the atimicrobial composition, [0035] The term “synergistic” as used herein refers tothe {teraction of two or more agents o that theircombined effect js greater than the sum of thei individual effoos [036] In an embodiment, an antimicrobial composition fan nchude a combination of three or more potentiating ‘agents a an ative ingredient [0037] Forexample at least onc ofthe tse or more poten ‘iating agents of the antimicrobial composition can be a sequestering agent. Preferred examples of sequestering ‘gels inch, but ae not mite 1, quinones, phosphorus acid derivatives, carboxylate sequestrants, natural protein sequesirants, and eyclodentrie sequestrants. Particularly pre- Temed examples of sequestering agents include S-hydrox- xyauinoline, ethylenediaminetetraestic acid (EDTA), L-hy- Groxyethylidene-1,1-liphosphonie acid (HEDP), sodium pyrophosphate, potassium hypophosphite, sodium tripoly- phosphate, salicylic acid, 2-hydroxypropyka-eyclodextrin, hhypophosphorous acid, circ acid, and lactoferrin, [0038] Atleast one ofthe three oF more potentiating agents ‘of the antimicrobial composition ean be a carbohydrate or carboliydrate derivative, Preferred examples of carboby= rates or carbohydrate derivatives include, bu are not limited to, polyol ethers and esters, Particularly preferred examples ‘of carboliydrates or carbohydrate derivatives nce, but are ‘ot limited to, polysaccharides, oligosaccharides and fatty cid polyol esters. Particularly prefered examples of earbo- hydrates include 2-hydroxypropyl-cceyclodextin, chitosan, ‘ety! glacoside, and glycerol monocaprylae [0039] Atleast one ofthe three or more potentiating agents ‘ofthe antimicrobial composition can he a teqpene!terpensih Preferred terpene/terpenoids contin at least two isoprendid substructural unit. Particularly preferred examples of terpe- resiterpenoids include, but are not limited to, linaloa, Timonene, nerlidel,tolaro, and ura acid [0040] Atleast one ofthe three or more potentiating agents of the antimicrobial composition ean be an amine or amine derivative. Examples of amines or amine derivatives include, ‘ut ae not limited 10, amines, peptide, alkaloids, dyes with an amine functional group, amine oxides and quaternary ‘ammonium compounds. Prefered examples of amines oF famine derivatives inchide, but are not limited to, nisin, pip- fering, methylene blue, N.N-bis-(-aminopropyl\odeey- Tamine, cetyipyridinium chloride, Iniryl dimethylamine oxide, and sodium pyrthione [041] Atleast one ofthe three or more potentiating agents ‘ofthe antimicrobial composition can be qustemary amma ‘ium compound, Preferred examples of quaternary ammo- ‘ium compounds include, but are not limited to L-camitine and ADBACS (alkydimethy] benzyl ammonium chloride). 0042] Atleast one ofthe three or more potentiating agents of the antimicrobial composition ean be a plant-derived ol Preferred examples of plant-derived els include, but are not Jimited to, aly] bothiveyanate and earvaero [043] Atleast one ofthe three or more potentiating agents ‘ofthe antimicrobial composition ean bea sulfonate. Preferred ‘examples ofslfonates include, but are not Himited 0, nope thalenesulfonie acid snd sodium Hignostlfonate 0044) At east one ofthe three or more potentiating agents ofthe antimicrobial composition can be a phenol. Preferred ‘examples of phenols incixleone or more phenolic funetional roups, Particularly prefered exaniples of phenols include,