ANTIMICROBIAL COMPOSITION

Abstract: An antimicrobial, low toxicity, non-irritating composition comprises a blend of several bis-quaternary ammonium compounds optionally coprecipitated (1) with a copolymer of vinylpyrrolidone and an acrylamido or vinyl quaternary ammonium monomer, or (2) polyvinylpyrrolidone.

Description: ANTIMICROBIAL COMPOSITION In one embodiment, what is provided herein are antimicrobial compositions comprising: (a) a blend of bis-guaternary ammonium compounds selected from those represented by the formula: in which Z is —-CH 2 CΗ 2 0) n CH 2 CH 2 - where n is 1 or 2; or -CH 2 CH=CH-CH 2 -; and R± and R 2 are independently C 12 or C 14 -alky1; and X is a halogen such as Cl, Br or I; in the weight ratio of about 25% of the compound where both R^. an( R 2 are C 12 -alkyl; 50% of the compound where R^ is C 12 -alkyl and R 2 is C 14 -alkyl; and 25% of the compound where both R.^ and R 2 are C 14 -alkyl; the stated weight percents being + 20%; and (b) a copolymer of vinylpyrrolidone and an acrylamido or vinyl quaternary ammonium monomer coprecipitated or in admixture with (a) . Z in the formula can be -^-CH 2 CH 2 0—,— n and n is 2; and the monomer is an acrylamido quaternary ammonium monomer. These compositions exhibit excellent antibacterial activity, low toxicity, water solubility and a low irritation effect on the skin of the user. The several bis-quaternary ammonium compounds which comprise the blend composition (a) are made by reacting one mole of a selected dihalo compound selected from: XCH 2 CH 2 OCH 2 CH 2 X, XCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 X and XCH 2 CH=CHCH 2 X; where X is a halide such as Cl, Br and I, with 2 moles of dodecyldimethyl a ine, tetradecyldimethylamine or predetermined mixtures thereof. A typical reaction is the following: ClCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 Cl (1 mole) + 2C 12 H 25 N(CH 3 ) 2 ^ Accordingly, a reaction mixture of one mole of dodecyldimethyla ine, one mole of the tetradecyldimethylamine and one mole of the selected dichloro compound will provide the following blend compositions: BLEND COMPOSITION D Compound A Compound B Compound C BLEND COMPOSITION H Compound A 1 Compound B ' Compound C BLEND COMPOSITION L Compound A" Compound B" Compound C" where the stated percentages are + 20%; of course, by varying the relative amounts of starting materials, a blend of different percentages of the individual compounds may be obtained. Another way of introducing the quaternary nitrogen into the polymer structure is by using monomers with functionality, either tertiary amine or reactive alkylating groups which are quaternizable. The following vinyl ammonium monomers can be copolymerized with vinyl pyrrolidone by solution polymerization in isopropyl alcohol or by precipitation polymerization in cyclohexane or heptane and under conditions to provide low molecular weight copolymers, i.e. about 10,000 to about 20,000, suitable for coprecipitation or admixture with the blend of bis-quaternary ammonium compounds. Methacrylamidopropyl Trimethylammonium Chloride (MAPTAC) Cl Dodecyldimethylammonium Propyl Methacrylamide Bromide or Iodide Salts Dodecyldimethylammonium Propyl Acrylamide Bromide or Iodide Salts ) 11 CH 3 I /Br Dodecyldimethyl (Vinyl Benzyl) Ammonium Chloride Didecylmethyl (Vinyl Benzyl) Ammonium Chloride A preferred copolymer is the copolymer of vinylpyrrolidone and MAPTAC, which is known as GAFQUAT ® HS-100 resin (ISP) , and is supplied as a 20% aqueous solution. The coprecipitate product comprising the blend composition and copolymer usually is prepared by reacting predetermined amounts of a dilute aqueous solution of the blend composition and copolymer, usually from 90:10 to 10:90 wt. ratio of each, respectfully, and removing the solvent. The desired coprecipitate is formed as a solid product. These products exhibit an enhanced antimicrobial activity and reduced toxicity as compared to the individual compounds of the blend composition. Furthermore, they show excellent solubility in water, low toxicity and little irritation for the user. The antimicrobial compositions of the invention may be used as such; however, preferably they are admixed with inert materials as pharmaceutical and cosmetic formulations, e.g. in the form of powders, solutions, lotions, suspensions and the like. Typical inert additives include water, alcohols, starch, and the like. Active ingredients also may be included in the product, if desired. While the coprecipitate form of the antibacterial product of the invention is favored, admixtures of the blend and copolymer also may be used to prepare commercial compositions. The antimicrobial activity of the products herein are represented by their Minimum Inhibitory Concentration (MIC) against E.Coli, a Gram negative microorganism. Their effect on skin is indicated by an Irritation Index. These properties are presented in the Table below for the individual compounds in blend D and the invention composition of several D, H and L blend compositions coprecipitated in a 50:50 wt. ratio with with GAFQUAT ® HS-100. TABLE 1 Compound/Composition MIC Irritation Index A compound in D blend 100 B compound in D blend 50 C compound in D blend 125 D blend Of 25A/50B/25C 10 coprecipitated with GAFQUAT ® HS-100 (50:50) D blend of 40A/20B/40C 20 coprecipitated with GAFQUAT ® HS-100 (50:50) D blend of 33A/33B/33C 20 coprecipitated with GAFQUAT ® HS-100 (50:50) D blend ofl0A/80B/10C 20 coprecipitated with GAFQUAT ® HS-100 (50:50) H blend of 25A-/50B- /25C 1 30 coprecipitated with GAFQUAT ® HS-100 (50:50) L blend of 25A"/50B I •/25C ,■ 10 coprecipitated with GAFQUAT ® HS-100 (50:50) redness of skin, 1000 ppm active in water, scale of 1 to 10, with 10 being most irritating The LD 50 toxicity of the blend compositions, D, above, with the copolymer, are reduced by a factor of 5-20 as compared to the individual compounds in the blend, as shown in Table 2 below. TABLE 2 Compound/Composition i 5o (g/fo?) A compound in D blend 0.30 B compound in D blend 0.70 C compound in D blend 0.95 D blend of 25A/50B/25C 5.75 coprecipitated with GAFQUAT ® HS-100 (50:50) H blend of 25A I /50B , /25C 5.25 coprecipitated with GAFQUAT ® HS-100 (50:50) L blend of 25A ,, /50B"/25C" coprecipitated with GAFQUAT ® HS-100 (50:50) 6.25 Accordingly, the antibacterial activity of the compositions of the invention are up to 12.5 times more favorable than the individual compounds of the blend; the product containing the D blend shows only 1/3 to 1/4 as much irritation to the skin as the H and L blend products, respectively; and the blends are 5-20 less toxic than the individual compounds in the blends. EXAMPLE 1 Preparation of Bisquat Blend Composition A reaction solution of: l,2-bis(2-chloroethoxy) ethane 37.5 g. , 0.2 mole; Dodecyldimethylamine 42.6 g. , 0.2 mole; Tetradecyldimethylamine 48.4 g., 0.2 mole; Potassium Iodide 5 g. ; and Methanol 200 g. , was mixed well and heated to 90-l00°C. for 12 hours. Then the solvent was removed to give a heavy syrupy residue which was treated with acetone to precipitate out the . bis-quats blend composition in a yield of at least 95%. The composition comprised 25% by weight of A, 50% by weight of B and 25% by weight of C, above. EXAMPLE 2 Preparation of the Coprecipitate Product 90 g. of a 1% by weight aqueous solution of GAFQUAT ® HS-100 was mixed with 10 g. of the bis-quat blend of Example 1. Then water was removed under reduced pressure. A solid coprecipitate was formed which analyzed 10% by weight active bis-quat blend, and 50% by weight copolymer. In other embodiments, the antimicrobial blend composition of bis-quaternary ammonium compounds is selected from those represented by the in which Z is —f-CH 2 CH 2 0) n CH 2 CH 2 - where n is 1 (H Blend) or 2 (D Blend) ; or -CH 2 CH=CH-CH 2 - (L Blend) ; and R j L and R are independently C 12 or C 14 -alkyl; X~ is a halogen such as Cl, Br or I; and in the weight ratio of about 25% of the compound where both R.^ and R 2 are C 12 -alkyl; 50% of the compound where R.^ is C 12 -alkyl and R 2 is C 1 -alkyl; and 25% of the compound where both ^ and 2 are C 14 -alkyl; the stated weight percents being + 20%; and, optionally, including polyvinylpyrrolidone (PVP) as a coprecipitate or in admixture therewith. The blend composition with polyvinylpyrrolidone usually is prepared by reacting a dilute solution of the blend composition in alcohol or water, preferably methanol, with a dilute solution of the bisquat blend composition in the same solvent, and removing the solvent to form the desired coprecipitate solid product. More particularly, the blend coprecipitate compositions of the invention are prepared by refluxing the selected dichloro compound, the amines, and an alkali metal halide, in alcoholic solution, removing the solvent, precipitating the blend of bisquats in an organic solvent in substantially quantitative yield, and reacting a solution of the thus-prepared bisquat in methanol or water with a solution of soluble polyvinylpyrrolidone in the same solvent, and removing the solvent under reduced pressure to form the solid coprecipitate product. These blend compositions with polyvinylpyrrolidone exhibit an enhanced antimicrobial activity and reduced toxicity as compared to the individual compounds therein. Furthermore, they show excellent solubility in water, and less irritation to the user, as compared to the blend composition itself, that is, without polyvinylpyrrolidone. The antimicrobial compositions of the invention may be used as such, or, preferably, admixed with an inactive or inert component to prepare pharmaceutical formulations such as powders, solutions, lotions, suspensions and the like. Typical additives include water, alcohols, starch, etc. Other active ingredients may be included if desired. While the coprecipitate form is favored, mixtures of the blend composition and polyvinylpyrrolidone may be used as well. Typical antimicrobial activities, represented by their Minimum Inhibitory Concentration (MIC) , against E.Coli, a gram negative microorganism, is presented in the Table below for both the individual compounds in blend composition D and the D, H and L blend compositions with polyvinylpyrrolidone at different relative amounts of the compounds therein (as measured in a 10% active solution) . TABLE 3 Compound or Blend MIC A compound in D blend 100 C compound in D blend 125 B compound in D blend 50 D coprecipitate of 25A/50B/25C 5 composition with polyvinylpyrrolidone (50:50) D coprecipitate of 40A/20B/40C 35 composition with polyvinylpyrrolidone (50:50) D coprecipitate of 33A/33B/33C 30 composition with polyvinylpyrrolidone (50:50) D coprecipitate oflOA/80B/10C 25 composition with polyvinylpyrrolidone (50:50) H coprecipitate of 25A » /50B-/25C- 15 composition with polyvinylpyrrolidone (50:50) L coprecipitate of 25A ,, /50B"/25C" 5 composition with polyvinylpyrrolidone (50:50^ The MIC values of the blend-PVP coprecipitate compositions in the TABLE are up to 25 times more favorable than the individual compounds in the blend. The compositions of the invention also have increased water solubility than blends without PVP. The LD 50 toxicity of the D blend-PVP compositions above also is reduced by a factor of 5-6 as compared to the individual compounds in the blend, furthermore they exhibit a substantially reduced irritation to the skin as compared to the individual compounds or the blend without PVP. EXAMPLE 3 Preparation of Blend D-PVP Composition 1. A reaction solution of: l,2-bis(2-chloroethoxy) ethane 37.5 g. , 0.2 mole; Dodecyldimethylamine 42.6 g., 0.2 mole; Tetradecyldimethylamine 48.4 g. , 0.2 mole; Potassium Iodide 5 g. ; and Methanol 200 g. , was mixed well and heated to 90-100°C. for 12 hours. Then the solvent was removed to give a heavy syrupy residue which was treated with acetone to precipitate out the bisquats of the D blend composition in a yield of at least 95%. The blend composition comprised 25% by weight of A, 50% by weight of B and 25% by weight of C compounds. 2. A 10% by weight solution of PVP-CI in methanol was mixed with a 10% solution of the bisquat prepared above in methanol. The solvent then was removed under reduced pressure whereupon a solid coprecipitate was formed which analyzed 50% by weight active D bisquat blend and 50% by weight PVP. Typical antimicrobial activities, represented by their Minimum Inhibitory Concentration (MIC) against E.Coli, a gram negative microorganism, is presented in the Table below for both the individual compounds in blend composition D and the blend composition itself, with PVP, with different relative amounts of the A, B and C compounds therein (as measured in a 10% active solution) . TABLE 4 Compound or Blend MIC A compound in D blend 100 B compound in D blend 50 C compound in D blend 125 D blend of 25A/50B/25C composition 5 D blend of 40A/20B/40C composition 35 D blend of 33A/33B/33C composition 30 D blend of 10A/80B/10C composition 25 The MIC values of the D blend compositions in the TABLE are up to 25 times more favorable than the individual compounds in the blend. The LDt jQ toxicity of the blend composition D (without PVP) above, also is observed to be reduced by a factor of 5-6 as compared to the individual compounds.

Claims: WHAT IS CLAIMED IS: 1. An antimicrobial, low toxicity, non-irritating composition comprising (a) a blend of bis-quaternary ammonium compounds having the formula: in which Z is --CH 2 CH 2 0) n CH 2 CH 2 - where n is 1 or 2 ; or -CH 2 CH=CH-CH 2 -; and R-L and R 2 are independently C 12 or C 14 -alkyl; and X is a halogen such as Cl, Br or I; in the weight ratio of about 25% by weight of the compound where both R^ and R 2 are C 12 -alkyl; 50% by weight of the compound where R^ is C 12 -alkyl and R 2 is C 14 -alkyl; and 25% by weight of the compound where both R and R 2 are C 14 -alkyl; the stated weight percents being + 20%; and (b) a copolymer of polyvinylpyrrolidone and an acrylamido or vinyl quaternary ammonium monomer coprecipitated or in admixture with said blend. 2. A composition according to claim 1 wherein Z is —t_-CH 2 CH 0) n CH 2 CH 2 -, or n is 1 or 2, or Z is -CH 2 CH=CH-CH 2 -, or X is Cl or Br, or wherein said weight percentages are + 5-10%, optionally includes an inert component. 3. A composition according to claim 1 wherein said copolymer is coprecipitated with the blend of bis-quaternary ammonium compounds. 4. A composition according to claim 1 wherein (a) and (b) are present in about a 50:50 wt. ratio. 5. A composition according to claim 1 wherein said acrylamido quaternary ammonium monomer is methacrylamidopropyl trimethylammonium chloride. 6. A composition according to claim 1 wherein said acrylamido quaternary ammonium monomer is dodecyldimethylammonium propyl methacrylamide or acrylamide bromide"or iodide. 7. A composition according to claim 1 wherein said vinyl quaternary ammonium monomer is dodecyldimethyl (vinylbenzyl) ammonium chloride or didecylmethyl (vinylbenzyl) ammonium chloride. 8. A composition according to claim 1 wherein (b) is absent. 9. A composition according to claim 1 wherein PVP is substituted for (b) .

Inventors: MERIANOS JOHN J, MERIANOS, JOHN, J.
Applicants: ISP INVESTMENTS INC, ISP INVESTMENTS INC.
Application year: 1992
Main classification: A01N25
IPC codes: A01N33, C07C211, C07C217, C07C233, C08K5