Antimicrobial compositions

Abstract

An anti-microbial composition, comprising a chelator (such as EDTA and its salts), and a transport enhancer (such as Methyl Sufonyl Methane; MSM) is provided. Together, the combination of the two substances unexpectedly and beneficially inhibits bacterial or fungal biofilms when administered to an area of microbial infection. Preferred formulations include spray, lotion, solution, gel, cream, ointment, soap, deodorant, surgical rinse, or dental rinse.

What is claimed is: 
     
         1 . An antimicrobial formulation, comprising:
 a chelating agent or salts thereof;   a transport enhancer; and   an acceptable vehicle or base for such composition;   wherein the chelating agent and the transport enhancer are present in a proportion effective to bring about a significant reduction in bacterial and/or fungal biofilm on a surface to which it is applied, and   wherein the percentage of chelator is about 0.1% to 15% and the percentage of transport in the composition is about 0.1% to 40% by weight, respectively.   
     
     
         2 . The formulation of  claim 1 , wherein the transport enhancer is MSM. 
     
     
         3 . The formulation of  claim 1 , wherein the transport enhancer is DMSO. 
     
     
         4 . The formulation of  claim 2 , wherein the proportion of the chelator to MSM is in the range of about 10:1-1:20. 
     
     
         5 . The formulation of  claim 1 , wherein the composition comprises a formulation selected from solid, liquid, inhalant, spray, lotion, solution, gel, cream, ointment, surgical rinse, or dental rinse. 
     
     
         6 . The formulation of  claim 1 , wherein the chelating agent is selected from ethylenediamine tetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), cyclohexanediamine tetraacetic acid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA), diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonic acid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylene phosphonic acid (ArPA), citric acid, acetic acid and acceptable salts thereof, and any combinations thereof. 
     
     
         7 . The formulation of  claim 7 , wherein the EDTA salt is selected from diammonium EDTA, disodium EDTA, dipotassium EDTA, triammonium EDTA, trisodium EDTA, tripotassium EDTA, tetrasodium EDTA, tetrapotassium EDTA, calcium disodium EDTA, and combinations thereof. 
     
     
         8 . The formulation of  claim 1 , wherein the chelating agent is selected from phosphates, pyrophosphates, tripolyphosphates, and hexametaphosphates. 
     
     
         9 . The formulation of  claim 1 , wherein the chelating agent is a chelating antibiotic, chloroquine or tetracycline. 
     
     
         10 . The formulation of  claim 1 , wherein the chelating agent is a nitrogen-containing chelating agents containing two or more chelating nitrogen atoms within an imino group or in an aromatic ring, diimines, or 2,2′-bipyridines. 
     
     
         11 . The formulation of  claim 1 , wherein the chelating agent is a polyamine selected from cyclam (1,4,7,11-tetraazacyclotetradecane), N—(C 1  -C 30  alkyl)-substituted cyclams (e.g., hexadecyclam, tetramethylhexadecylcyclam), diethylenetriamine (DETA), spermine, diethylnorspermine (DENSPM), diethylhomo-spermine (DEHOP), deferoxamine (N′-{5-[Acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamide, or N′-[5-(Acetyl-hydroxy-amino)pentyl]-N-[5-[3-(5-aminopentyl-hydroxy-carbamoyl) propanoylamino]pentyl]-N-hydroxy-butane diamide), desferrioxamine B, desferoxamine B, DFO-B, DFOA, DFB, desferal, deferiprone, pyridoxal isonicotinoyl hydrazone (PIH), salicylaldehyde isonicotinoyl hydrazone (SIH), ethane-1,2-bis(N-1-amino-3-ethylbutyl-3-thiol). 
     
     
         12 . The formulation of  claim 1 , wherein the chelating agent is a EDTA-4-aminoquinoline conjugate selected from ([2-(Bis-ethoxycarbonylmethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(Bis-ethoxycarbonylmethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(Bis-ethoxycarbonylmethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bis-ethoxymethyl-amino)-ethyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([2-(Bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([3-(Bis-ethoxymethyl-amino)-propyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester, ([4-(Bis-ethoxymethyl-amino)-butyl]-{[2-(7-chloro-quinolin-4-ylamino)-ethylcarbamoyl]-methyl}-amino)-acetic acid ethyl ester. 
     
     
         13 . The formulation of  claim 1 , wherein the chelating agent is a tetrasodium salt of iminodisuccinic acid. 
     
     
         14 . The formulation of  claim 1 , wherein the chelating agent is poly-asparatic acid or a salt thereof. 
     
     
         15 . The formulation of  claim 1 , wherein the chelating agent is a tetra sodium salt of L-glutamic acid N,N-diacetic acid. 
     
     
         16 . The formulation of  claim 1 , wherein the chelating agent is a natural chelator selected from citric acid, phytic acid, lactic acid, acetic acid and their salts and curcumin. 
     
     
         17 . The formulation of  claim 1 , further comprising an antibiotic agent. 
     
     
         18 . The formulation of  claim 17 , wherein the antibiotic is antibacterial or antifungal. 
     
     
         19 . The formulation of  claim 1 , wherein the formulation is for oral administration. 
     
     
         20 . The formulation of  claim 19 , wherein the formulation is a lozenge or a mouth wash. 
     
     
         21 . The formulation of  claim 1 , wherein the formulation is for parenteral administration. 
     
     
         22 . The formulation of  claim 1 , wherein the formulation is for topical administration. 
     
     
         23 . The formulation of  claim 1 , wherein the formulation is an ointment, cream, or lotion. 
     
     
         24 . The formulation of  claim 1 , wherein the formulation is for intra-nasal administration. 
     
     
         25 . The formulation of  claim 1 , wherein the formulation is for timed release. 
     
     
         26 . A method for inhibiting a biofilm associated bacterial infection comprising administering the formulation of  claim 1  in combination with or prior to administration of an antibiotic. 
     
     
         27 . A medical device coated with the formulation of  claim 1 . 
     
     
         28 . The medical device of  claim 27 , wherein the medical device is an implantable device. 
     
     
         29 . The medical device of  claim 28 , wherein the medical device is selected from the group consisting of a central venous catheter, an intravascular catheter, an urinary catheter, a Hickman catheter, a peritoneal dialysis catheter, an endrotracheal catheter, a mechanical heart valve, a cardiac pacemaker, an arteriovenous shunt, a schleral buckle, a prosthetic joint, a tympanostomy tube, a tracheostomy tube, a voice prosthetic, a penile prosthetic, an artificial urinary sphincter, a synthetic pubovaginal sling, a surgical suture, a bone anchor, a bone screw, an intraocular lens, a contact lens, an intrauterine device, an aortofemoral graft, and a vascular graft. 
     
     
         30 . The medical device of  claim 30 , wherein the medical device is a surgical instrument. 
     
     
         31 . The medical device of  claim 30 , wherein the surgical instrument is a clamp, forceps, scissor, skin hook, tubing, needle, retractor, scaler, drill, chisel, rasp, or saw. 
     
     
         32 . A wound dressing impregnated with the formulation of  claim 1 . 
     
     
         33 . The wound dressing of  claim 32 , wherein the wound dressing is a sponge, gauze, or catheter shield. 
     
     
         34 . A transdermal patch comprising the formulation of  claim 1 . 
     
     
         35 . A method for promoting detachment of bacterial or fungal cells from a biofilm comprising contacting bacterial cells with the formulation of  claim 1 . 
     
     
         36 . A method of inhibiting infection on a medical device or surgical instrument by bacteria or fungi comprising contacting the medical device or surgical instrument with the formulation of  claim 1 . 
     
     
         37 . A method of inhibiting infection on a medical device or surgical instrument by bacteria or fungi comprising coating the medical device or surgical instrument with the formulation of  claim 1 . 
     
     
         38 . A method of inhibiting infection on a medical device or surgical instrument by bacteria or fungi comprising bathing the medical device or surgical instrument in a solution comprising the formulation of  claim 1 . 
     
     
         39 . A method of inhibiting or treating bacterial or fungal infections comprising administering a pharmaceutically acceptable composition comprising the formulation of  claim 1 . 
     
     
         40 . The method of  claim 39  wherein the bacteria is selected from the group consisting of  Acidothermus cellulyticus, Actinomyces odontolyticus, Alkaliphilus metalliredigens, Alkaliphilus oremlandii, Arthrobacter aurescens, Bacillus amyloliquefaciens, Bacillus clausii, Bacillus halodurans, Bacillus licheniformis, Bacillus pumilus, Bacillus subtilis, Bifidobacterium adolescentis, Bifidiobacterium longum, Caldicellulosiruptor saccharolyticus, Carboxydothermus hydrogenoformans, Clostridium acetobutylicum, Clostridium beijerinckii, Clostridium botulinum, Clostridium cellulolyticum, Clostridium difficile, Clostridium kluyveri, Clostridium leptum, Clostridium novyi, Clostridium perfringens, Clostridium tetani, Clostridium thermocellum, Corynebacterium diphtheriae, Corynebacterium efficiens, Corynebacterium glutamicum, Corynebacterium jeikeium, Corynebacterium urealyticum, Desulfitobacterium hafniense, Desulfotomaculum reducens, Eubacterium ventriosum, Exiguobacterium sibiricum, Fingoldia magna, Geobacillus kaustophilus, Geobacillus  the rmodenitrificans,  Janibacter  sp.,  Kineococcus radiotolerans, Lactobacillus fermentum, Listeria monocytogenes, Listeria innocua, Listeria welshimeri, Moorella thermoacetica, Mycobacterium avium, Mycobacterium bovis, Mycobacterium gilvum, Mycobacterium leprae, Mycobacterium paratuberculosis, Mycobacterium smegmatis, Mycobacterium tuberculosis, Mycobacterium ulcerans, Mycobacterium vanbaalenii, Nocardioides  sp.,  Nocardia farcinica, Oceanobacillus iheyensis, Pelotomaculum thermopropionicum, Rhodococcus  sp.,  Saccharopolyspora erythraea,  coagulase-negative  Staphylococcus  species,  Staphylococcus aureus, methicillin resistant Staphylococcus aureus  (MRSA),  Staphylococcus epidermidis,  methicillin resistant  Staphylococcus epidermidis  (MRSE),  Streptococcus agalactiae, Streptococcus gordonii, Streptococcus mitis, Streptococcus oxalis, Streptococcus pneumoniae, Streptococcus sanguinis, Streptococcus suis, Streptomyces avermitilis, Streptomyces coelicolor, Thermoanaerobacter ethanolicus, Thermoanaerobacter tengcongensis,  and combinations thereof. 
     
     
         41 . The method of  claim 39  wherein the bacteria is a gram-positive bacteria. 
     
     
         42 . A bandage impregnated with a safe and effective amount of the formulation of  claim 1 , wherein the bandage inhibits the formation of a biofilm on the skin. 
     
     
         43 . A personal cleansing composition comprising an effective amount of the formulation of  claim 1 , wherein the personal cleansing composition inhibits formation of a biofilm on the skin. 
     
     
         44 . The personal cleansing composition of  claim 43 , wherein the composition is a surgical scrub, shower gel, body wash, or soap. 
     
     
         45 . A hard surface cleaning composition comprising an effective amount of the formulation of  claim 1 , wherein the composition inhibits formation of a biofilm on the hard surface. 
     
     
         46 . A dental rinse for inhibiting formation of a biofilm, the dental rinse comprising an effective amount of the formulation of  claim 1 . 
     
     
         47 . The formulation of  claim 1 , wherein the formulation is suitable for application to a surface, the formulation comprising:
 about 0.4-15% of chelator;   about 0.5-30% of MSM;   one or more thickening and gelling agents;   10-99% water; and   optionally contains surfactants, detergents and/or soaps.   
     
     
         48 . The formulation of  claim 47 , comprising:
 about1-5% of chelator;   about 1-10% of MSM;   0.1-6% of one or more thickening agents; and   80-97% water.   
     
     
         49 . The formulation of  claim 1 , wherein the formulation is suitable for oral application, the formulation comprising:
 about 0.4-8% of a chelator; and   about 0.5-16% of MSM.