Abstract:
A synergistic microbicidal composition. The composition comprises: (a) silver ion; and (b) diiodomethyl-p-tolylsulfone; wherein a weight ratio of silver to diiodomethyl-p-tolylsulfone is from 1: 1/0.008 to 1/0.1, 1/0.13 to 1/8 or 1/120 to 1/280.

Description:
[0001]    The present invention relates to microbicide combinations containing silver and diiodomethyl-p-tolylsulfone (DIMTS). 
         [0002]    A combination of DIMTS with zinc is disclosed in U.S. App. No. 2006/0171911. However, this reference does not teach the combination claimed in the present application. 
         [0003]    Use of combinations of at least two antimicrobial compounds can broaden potential markets, reduce use concentrations and costs, and reduce waste. In some cases, commercial antimicrobial compounds cannot provide effective control of microorganisms, even at high use concentrations, due to weak activity against certain types of microorganisms, e.g., those resistant to some antimicrobial compounds. Combinations of different antimicrobial compounds are sometimes used to provide overall control of microorganisms in a particular end use environment. The problem addressed by this invention is to provide additional synergistic combinations of antimicrobial compounds. 
       STATEMENT OF THE INVENTION 
       [0004]    The present invention is directed to a synergistic microbicidal composition. The composition comprises: (a) silver ion; and (b) diiodomethyl-p-tolylsulfone; wherein a weight ratio of silver to diiodomethyl-p-tolylsulfone is from 1: 1/0.008 to 1/0.1, 1/0.13 to 1/8 or 1/120 to 1/280. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0005]    Preferably, the silver ion (Ag(I)) is present in the composition as a complex with a polymeric delivery system, preferably a copolymer comprising polymerized units of a monomer X and a monomer Y; wherein monomer X is an ethylenically unsaturated compound having a substituent group selected from an unsaturated or aromatic heterocyclic group having at least one hetero atom selected from N, O and S; preferably the substituent group is selected from an unsaturated or aromatic heterocyclic group having at least one hetero N atom; and wherein monomer Y is an ethylenically unsaturated compound selected from carboxylic acids, carboxylic acid salts, carboxylic acid esters (preferably alkyl esters, hydroxyalkyl esters, polyethylene glycol esters, etc.), organosulfuric acids, organosulfuric acid salts, sulfonic acids, sulfonic acid salts, phosphonic acids, phosphonic acid salts, vinyl esters (e.g., vinyl C 1 -C 8  alkanoates), (meth)acrylamides, C 8 -C 20  aromatic monomers containing at least one exocyclic ethylenic unsaturation and combinations thereof. 
         [0006]    The term “copolymer” as used herein refers to polymers polymerized from at least two different monomers. Percentages herein are by weight, unless specified otherwise. Monomer unit percentages are based on total copolymer weight. 
         [0007]    The term “aqueous” as used herein means water and mixtures composed substantially of water and water miscible solvents. 
         [0008]    The use of the term “(meth)” followed by another term such as acrylic, acrylate, acrylamide, etc., as used herein and in the appended claims, refers to, for example, both acrylic and methacrylic; acrylate and methacrylate; acrylamide and methacrylamide; etc. 
         [0009]    The glass transition temperature (“Tg”) for the copolymers and pressure sensitive adhesive formulations of the present invention may be measured by differential scanning calorimetry (DSC) taking the mid-point in the heat flow versus temperature transition as the Tg value. Preferably, the copolymer comprises at least 15 wt % of monomer X derived units. Preferably, the copolymer comprises at least 20 wt % of monomer X derived units, preferably at least 25 wt %, preferably at least 30 wt %, preferably at least 35 wt %, preferably at least 40 wt %. Preferably, the copolymer comprises no more than 60 wt % of monomer X derived units, preferably no more than 55 wt %, preferably no more than 50 wt %. 
         [0010]    Preferably, monomer X is selected from vinylimidazoles, vinylimidazolines, vinylpyridines, vinylpyrroles, derivatives thereof and combinations thereof. Preferably, monomer X is selected from vinylimidazoles, vinylpyridines, derivatives thereof and combinations thereof. Preferably, monomer X is selected from N-vinylimidazole, 2-vinylpyridine, 4-vinylpyridine and combinations thereof. Preferably, monomer X is N-vinylimidazole (VI). 
         [0011]    Preferably, monomer Y is selected from carboxylic acids, carboxylic acid salts, carboxylic acid esters, organosulfuric acids, organosulfuric acid salts, sulfonic acids, sulfonic acid salts, phosphonic acids, phosphonic acid salts, vinyl esters, (meth)acrylamides, C 8 -C 20  aromatic monomers containing at least one exocyclic ethylenic unsaturation and combinations thereof. Preferably, monomer Y is selected from carboxylic acids, carboxylic acid esters (e.g., alkyl (meth)acrylates), (meth)acrylamides, C 8 -C 20  aromatic monomers containing at least one exocyclic ethylenic unsaturation and combinations thereof. Preferably, monomer Y is selected from acrylic acid (AA), methacrylic acid, itaconic acid, maleic acid, fumaric acid, methyl (meth)acrylate, ethyl (meth)acrylate, propyl (meth)acrylate, isopropyl acrylate, n-butyl (meth)acrylate, isobutyl (meth)acrylate, 2-ethylhexyl (meth)acrylate, decyl (meth)acrylate, lauryl (meth)acrylate, stearyl (meth)acrylate, styrene, vinyltoluene, α-methylstyrene and combinations thereof. Preferably, monomer Y comprises at least one C 2 -C 8  alkyl (meth)acrylate, alternatively n-butyl (meth)acrylate, alternatively monomer Y comprises n-butyl acrylate (BA) and acrylic acid. 
         [0012]    Preferably, the copolymer comprises no more than 5 wt % of units derived from ethylenically unsaturated monomer containing an epoxide function, preferably no more than 1 wt %, preferably no more than 0.5 wt %, preferably no more than 0.1 wt %, preferably no more than 0.05 wt %. 
         [0013]    Preferably, the composition comprising a copolymer has a pH from 3.5 to 10, preferably from 4 to 10, preferably from 4 to 10, preferably from 4.5 to 10, preferably from 4 to 9, preferably from 4 to 8, preferably from 4.5 to 7.5, preferably from 5 to 10, preferably from 6 to 10, preferably from 7 to 10, preferably from 8 to 10. 
         [0014]    Preferably, the composition comprising a copolymer comprises at least 20 wt % solids. Preferably, the composition comprises at least 25 wt % solids. Preferably, the composition comprises at least 30 wt % solids. 
         [0015]    If the copolymer comprises polymerized units derived from a crosslinker, preferably the crosslinkers are multi-ethylenically unsaturated monomers, preferably, selected from 1,4-butanediol diacrylate; 1,4-butanediol dimethacrylate; 1,6-hexanediol diacrylate; 1,1,1-trimethylol propane triacrylate; 1,1,1-trimethylol propane trimethacrylate; allyl methacrylate; divinylbenzene; and N-allyl acrylamide. Preferably, the crosslinker derived units are derived from crosslinker selected from 1,1,1-trimethylol propane trimethacrylate. If crosslinkers are present, preferably the copolymer comprises 0.01 to 10 wt % (based on solids) crosslinker, preferably 0.01 to 5 wt %, preferably 0.01 to 1 wt %. 
         [0016]    Preferably, the copolymer comprises from 1.5 wt % to 20 wt % silver based on total weight of copolymer and silver, alternatively from 2.5 wt % to 15 wt %, alternatively from 5 wt % to 11.5 wt %, alternatively from 6.5 wt % to 8.5 wt %. Silver is in the form of Ag(I) ion, which typically is introduced in the form of silver nitrate. Methods for preparation of the copolymer have been disclosed previously, e.g., in U.S. Pat. No. 7,335,613. 
         [0017]    The specific amount of the composition of this invention necessary to inhibit or control the growth of microorganisms in an application will vary. Typically, the amount of the composition of the present invention is sufficient to control the growth of microorganisms if it provides from 0.1 to 25,000 ppm (parts per million) active ingredient of the composition (as silver plus co-biocide combined). It is preferred that the active ingredients of the composition be present in the locus in an amount of at least 0.1 ppm, more preferably at least 5 ppm, more preferably at least 50 ppm and most preferably at least 500 ppm. In one embodiment of the invention, the active ingredients are present in an amount of at least 2,000 ppm. It is preferred that the active ingredients of the composition be present in the locus in an amount of no more than 20,000 ppm, more preferably no more than 15,000 ppm, more preferably no more than 5,000 ppm. Preferably, the active ingredients are present in an amount of no more than 15,000 ppm, more preferably no more than 8,000 ppm, and most preferably no more than 3,000 ppm. 
       EXAMPLES 
       [0018]    The silver-containing copolymer tested in these Examples comprises a polymer having 45% BA monomer units, 45% VI monomer units and 10% AA monomer units, based on polymer weight, and containing 7.8% silver ion, based on total weight of polymer and silver. The silver-containing polymer was formulated in water at 39% solids and pH 11. 
         [0019]    The combinations were evaluated for synergy by determining the synergy index (S.I.) of the combination. The Synergy index calculated is based on minimum inhibitory concentrations (MIC) of two biocides (A and B) alone and in combinations. The lower the S.I. value, the better the synergy. 
         [0020]    High Resolution Minimum Inhibitory Concentration (HRMIC) method was performed to determine the potential for synergy of the combinations. The tests organisms were gram negative bacteria ( Pseudomonas aeruginosa ), Gram positive bacteria ( Staphylococcus aureus ), yeast ( Candida albicans ) and mold ( Aspergillus niger ). Contact time for the bacteria was 24 and 48 hours, yeast was 48 and 72 hrs, 3 and 7 days for mold. The test was carried out in 96well microtiter plates. 
         [0021]    The test results for demonstration of synergy of the MIC combinations are shown below in Tables 1 through 4. Each table shows the combinations of two components results against the microorganisms tested with incubation times; the end-point activity in ppm measured by the MIC for compound A alone (CA), for component B alone (CB), and the mixture (Ca) and (Cb); the calculated SI value; and the range of synergistic ratios for each combination tested. 
         [0000]        Ca/CA+Cb/CB =Synergy Index(“SI”)
 
       Wherein: 
       [0000]    
       
         
           
             CA=concentration of compound A in ppm, acting alone, which produced an end point (MIC of Compound A). 
             Ca=concentration of compound A in ppm, in the mixture, which produced an end point. 
             CB=concentration of compound B in ppm, acting alone, which produced an end point (MIC of Compound B). 
             Cb=concentration of compound B in ppm, in the mixture, which produced an end point. 
           
         
       
     
         [0026]    When the sum of Ca/CA and Cb/CB is greater than one, antagonism is indicated. When the sum is equal to one, additivity is indicated, and when less than one, synergism is demonstrated. 
         [0000]    
       
         
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
               
               
                 Preservatives Used 
               
             
          
           
               
                 Abbreviations 
                 Active ingredient 
                 Supplier 
                 AI % 
                 Solvent 
               
               
                   
               
             
          
           
               
                 silver-containing 
                 Silver 
                 The Dow 
                 3 
                 MQ H 2 O 
               
               
                 copolymer 
                   
                 Chemical Co. 
                   
                   
               
               
                 AMICAL ™ 48 
                 Diiodomethyl-p- 
                 The Dow 
                 95 
                 Ethanol 
               
               
                 biocide 
                 tolysulfone (DIMTS) 
                 Chemical Co. 
                   
                   
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Inoculums Used 
               
               
                 Inoculum Size of organisms ( CFU/ml ) 
               
             
          
           
               
                 
                   Staphylococcus. 
                 
                 
                   Pseudomonas 
                 
                 
                   Aspergillus  
                 
                 
                   Candida 
                 
               
               
                 
                   aureus 
                 
                   aeruginosa  ATCC # 
                 
                   niger 
                 
                 
                   albicans 
                 
               
               
                 ATCC# 6538 
                 15442 
                 ATCC# 16404 
                 ATCC#10203 
               
               
                   
               
               
                 1.2 × 10 7   
                 1.2 × 10 7   
                 1.2 × 10 5   
                 5.3 × 10 5   
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
             
           
               
                   
               
               
                 Media Used 
               
               
                 Media Used for testing 
               
             
          
           
               
                 
                   Staphylococcus 
                 
                 
                   Pseudomonas 
                 
                 
                   Aspergillus 
                 
                 
                   Candida 
                 
               
               
                 
                   aureus 
                 
                   aeruginosa  ATCC # 
                 
                   niger 
                 
                 
                   albicans 
                 
               
               
                 ATCC# 6538 
                 15442 
                 ATCC# 16404 
                 ATCC#10203 
               
               
                   
               
               
                 TSB 
                 TSB 
                 PDB 
                 PDB 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 1 
               
               
                   
                   
               
               
                   
                 Test 
                 Contact 
                   
                   
                   
                   
               
               
                   
                 Organisms 
                 Time 
                 Ca 
                 Cb 
                 S.I. 
                 Ca:Cb 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 
                   A. niger 
                 
                 3rd day 
                 5 
                 — 
                 — 
                 — 
               
               
                   
                 ATCC 
                   
                 — 
                 0.3  
                 — 
                 — 
               
               
                   
                 #16404 
                   
                   
                   
                   
                   
               
               
                   
                   
                   
                 2.5 
                 0.02 
                 0.57 
                 1:0.0080 
               
               
                   
                   
                   
                 2.5 
                 0.1 
                 0.83 
                 1:0.0400 
               
               
                   
                   
                   
                 2.5 
                 0.2  
                 1.17 
                 1:0.0800 
               
               
                   
                   
                   
                 1.25 
                 0.06 
                 0.45 
                 1:0.0480 
               
               
                   
                   
                   
                 1.25 
                 0.1  
                 0.58 
                 1:0.0800 
               
               
                   
                   
                   
                 1.25 
                 0.2  
                 0.92 
                 1:0.1600 
               
               
                   
                   
                   
                 0.65 
                 0.3  
                 1.13 
                 1:0.4615 
               
               
                   
                   
                   
                 0.35 
                 0.3  
                 1.07 
                 1:0.8571 
               
               
                   
                   
                   
                 0.17 
                 0.3  
                 1.03 
                 1:1.7647 
               
               
                   
                   
                 7th day  
                 5 
                 — 
                 — 
                 — 
               
               
                   
                   
                   
                 — 
                 0.5  
                 — 
                 — 
               
               
                   
                   
                   
                 2.5 
                 0.03 
                 0.56 
                 1:0.0120 
               
               
                   
                   
                   
                 2.5 
                 0.2  
                 0.9 
                 1:0.0800 
               
               
                   
                   
                   
                 2.5 
                 0.3  
                 1.1 
                 1:0.1200 
               
               
                   
                   
                   
                 1.25 
                 0.4  
                 1.05 
                 1:0.3200 
               
               
                   
                   
                   
                 0.65 
                 0.4  
                 0.93 
                 1:0.6154 
               
               
                   
                   
                   
                 0.65 
                 0.5  
                 1.13 
                 1:0.7692 
               
               
                   
                   
                   
                 0.35 
                 0.5  
                 1.07 
                 1:1.4286 
               
               
                   
                   
                   
                 0.17 
                 0.5  
                 1.03 
                 1:2.9412 
               
               
                   
                   
               
               
                   
                 Ca: component in ppm AI (silver ion) of Silver-containing copolymer 
               
               
                   
                 Cb: component in ppm AI of DIMTS 
               
               
                   
                 Note: 
               
               
                   
                 MIC alone (CA and CB) is on the upper rows. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
               
                   
               
               
                 Test Organisms 
                 Contact Time 
                 Ca 
                 Cb 
                 S.I. 
                 Ca:Cb 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   C. albicans 
                 
                 48 hrs 
                 20 
                 — 
                 — 
                 — 
               
               
                 ATCC #10203 
                   
                 — 
                 20 
                 — 
                 — 
               
               
                   
                   
                 10 
                 0.08 
                 0.50 
                 1:0.0080 
               
               
                   
                   
                 10 
                 0.8 
                 0.54 
                 1:0.0800 
               
               
                   
                   
                 10 
                 10 
                 1.00 
                 1:1.0000 
               
               
                   
                   
                 5 
                 0.5 
                 0.28 
                 1:0.1000 
               
               
                   
                   
                 5 
                 5 
                 0.50 
                 1:1.0000 
               
               
                   
                   
                 5 
                 10 
                 0.75 
                 1:2.0000 
               
               
                   
                   
                 5 
                 20 
                 1.25 
                 1:4.0000 
               
               
                   
                   
                 2.5 
                 20 
                 1.13 
                 1:8.0000 
               
               
                   
                   
                 1.25 
                 20 
                 1.06 
                  1:16.0000 
               
               
                   
                   
                 0.65 
                 20 
                 1.03 
                  1:30.7692 
               
               
                   
                   
                 0.35 
                 20 
                 1.02 
                  1:57.1429 
               
               
                   
                   
                 0.17 
                 20 
                 1.01 
                  1:117.6471 
               
               
                   
                 72 hrs 
                 20 
                 — 
                 — 
                 — 
               
               
                   
                   
                 — 
                 30 
                 — 
                 — 
               
               
                   
                   
                 10 
                 0.08 
                 0.50 
                 1:0.0080 
               
               
                   
                   
                 10 
                 8 
                 0.77 
                 1:0.8000 
               
               
                   
                   
                 10 
                 10 
                 0.83 
                 1:1.0000 
               
               
                   
                   
                 10 
                 20 
                 1.17 
                 1:2.0000 
               
               
                   
                   
                 5 
                 0.4 
                 0.26 
                 1:0.0800 
               
               
                   
                   
                 5 
                 4 
                 0.38 
                 1:0.8000 
               
               
                   
                   
                 5 
                 10 
                 0.58 
                 1:2.0000 
               
               
                   
                   
                 5 
                 20 
                 0.92 
                 1:4.0000 
               
               
                   
                   
                 5 
                 30 
                 1.25 
                 1:6.0000 
               
               
                   
                   
                 2.5 
                 20 
                 0.79 
                 1:8.0000 
               
               
                   
                   
                 1.25 
                 30 
                 1.06 
                  1:24.0000 
               
               
                   
                   
                 0.65 
                 30 
                 1.03 
                  1:46.1538 
               
               
                   
                   
                 0.35 
                 30 
                 1.02 
                  1:85.7143 
               
               
                   
                   
                 0.17 
                 30 
                 1.01 
                  1:176.4706 
               
               
                   
               
               
                 Ca: component in ppm AI of Silver-containing copolymer 
               
               
                 Cb: component in ppm AI of DIMTS 
               
               
                 Note: 
               
               
                 MIC alone (CA and CB) is on the upper rows. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Test 
                 Contact 
                   
                   
                   
                   
               
               
                 Organisms 
                 Time 
                 Ca 
                 Cb 
                 S.I. 
                 Ca:Cb 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   Ps. aeruginosa 
                 
                 24 hrs 
                 10 
                 — 
                 — 
                 — 
               
               
                 ATCC 
                   
                 — 
                 &gt;1000 
                 — 
                 — 
               
               
                 #15442 
                   
                   
                   
                   
                   
               
               
                   
                   
                 5 
                 6 
                 0.51 
                 1:1.2000  
               
               
                   
                   
                 5 
                 60 
                 0.56 
                 1:12.0000  
               
               
                   
                   
                 5 
                 400 
                 0.90 
                 1:80.0000  
               
               
                   
                   
                 5 
                 500 
                 1.00 
                 1:100.0000 
               
               
                   
                   
                 2.5 
                 200 
                 0.45 
                 1:80.0000  
               
               
                   
                   
                 2.5 
                 300 
                 0.55 
                 1:120.0000 
               
               
                   
                   
                 2.5 
                 400 
                 0.65 
                 1:160.0000 
               
               
                   
                   
                 2.5 
                 500 
                 0.75 
                 1:200.0000 
               
               
                   
                   
                 2.5 
                 700 
                 0.95 
                 1:280.0000 
               
               
                   
                   
                 2.5 
                 800 
                 1.05 
                 1:320.0000 
               
               
                   
                   
                 1.25 
                 1000 
                 1.13 
                 1:800.0000 
               
               
                   
               
               
                 Ca: component in ppm AI of Silver-containing copolymer 
               
               
                 Cb: component in ppm AI of DIMTS 
               
               
                 Note: 
               
               
                 MIC alone (CA and CB) is on the upper rows. 
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Test 
                 Contact 
                   
                   
                   
                   
               
               
                 Organisms 
                 Time 
                 Ca 
                 Cb 
                 S.I. 
                 Ca:Cb 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 
                   S. aureus  
                 
                 24 hrs 
                 10 
                 — 
                 — 
                 — 
               
               
                 ATCC #6538 
                   
                 — 
                 30 
                 — 
                 — 
               
               
                   
                   
                 5 
                 10 
                 0.83 
                 1:2.0000  
               
               
                   
                   
                 5 
                 20 
                 1.17 
                 1:4.0000  
               
               
                   
                   
                 2.5 
                 20 
                 0.92 
                 1:8.0000  
               
               
                   
                   
                 2.5 
                 30 
                 1.25 
                 1:12.0000 
               
               
                   
                   
                 1.25 
                 30 
                 1.13 
                 1:24.0000 
               
               
                   
                 48 hrs 
                 40 
                 — 
                 — 
                 — 
               
               
                   
                   
                 — 
                 400 
                 — 
                 — 
               
               
                   
                   
                 30 
                 4 
                 0.76 
                 1:0.1333  
               
               
                   
                   
                 30 
                 10 
                 0.78 
                 1:0.3333  
               
               
                   
                   
                 30 
                 40 
                 0.85 
                 1:1.3333  
               
               
                   
                   
                 30 
                 100 
                 1.00 
                 1:3.3333  
               
               
                   
                   
                 30 
                 200 
                 1.25 
                 1:6.6667  
               
               
                   
                   
                 20 
                 40 
                 0.60 
                 1:2.0000  
               
               
                   
                   
                 20 
                 60 
                 0.65 
                 1:3.0000  
               
               
                   
                   
                 20 
                 100 
                 0.75 
                 1:5.0000  
               
               
                   
                   
                 20 
                 200 
                 1.00 
                 1:10.0000 
               
               
                   
                   
                 10 
                 100 
                 0.50 
                 1:10.0000 
               
               
                   
                   
                 10 
                 300 
                 1.00 
                 1:30.0000 
               
               
                   
                   
                 10 
                 400 
                 1.25 
                 1:40.0000 
               
               
                   
               
               
                 Ca: component in ppm AI of Silver-containing copolymer 
               
               
                 Cb: component in ppm AI of DIMTS 
               
               
                 Note: 
               
               
                 MIC alone (CA and CB) is on the upper rows. 
               
             
          
         
       
     
         [0027]    The data demonstrate that there is an unexpected synergistic interaction between silver and DIMTS at ratios of 1/0.008 to 1/0.1 ( C. albicans,  48 hr.), 1/0.13 to 1/8 ( S. aureus,  48 hr., 1/0.13-1/5 &amp;  C. albicans,  72 hr., 1/1-1/8) and 1/120 to 1/280 ( Ps. aeruginosa).