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Publication numberUS3890242 A
Publication typeGrant
Publication dateJun 17, 1975
Filing dateMar 30, 1973
Priority dateJan 17, 1972
Also published asDE2216725A1, US3753990, US3824307
Publication numberUS 3890242 A, US 3890242A, US-A-3890242, US3890242 A, US3890242A
InventorsJohn Downing Curry
Original AssigneeProcter & Gamble
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Antibacterial detergent compositions containing phenylbismuth bis(2-pyridinethiol 1-oxide)
US 3890242 A
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Description  (OCR text may contain errors)

Unlted States Patent 11 1 1111 3,890,242 Curry 5] June 17, 1975 1 ANTIBACTERIAL DETERGENT [51] Int. Cl Cl 1d 3/48 COMPOSITIONS CONTAINING [58] Field of Search 252/D1G. 16, 206, 207, PHI-INYLBISMUTH BIS(2-PYRIDINETHIOL lG- 13, DIG. 5; 2 /245 l-OXIDE) [75] Inventor: John Downing Curry, Oxford, Ohio [56] References Cited [73] Assignee: Procter & Gamble Company, UNITED STATES PATENTS Cincinnati Ohio 3,239,411 3/1966 Lecbnck 260/270 R 3,281,366 10/1966 Judge et a1 252/106 X [22] Filed: Mar. 30, 1973 3,321,480 5/1967 Schroder ct a1.... 260/270 R 3,583,999 6/1971 Damico 260/270 R [211 PP N04 346,396 3,835,057 9/1974 Cheng et a1.... 252/107 Related US. Application Data [60] Division of Ser. No. 218,584, Jan. 17, 1972, Pat. No. W Padgett 3,753,990, which is a continuation-in-part of Ser. No. Assistant EXammer E' Mlllcr 98,086, Dec. 14, 1970, abandoned, Attorney, Agent, or Firm--Ronald L. Hemmgway;

Robert B. Aylor; Richard C. Witte [30] Foreign Application Priority Data Apr. 4, 1972 Netherlands 7204437 [57] ABSTRACT Apr. 7, 1972 France 72.12388 phenylbismuth bis(2 pyridinethi0l l oxide) a new 1972 Germany "22/1672 antibacterial and antifungal compound, and composi- Apr. 10, 1972 Sweden 4611/72 tions containing Same Apr. 13, 1972 United Kingdom 17088/72 6 Claims, N0 Drawings [52] US. Cl. 252/107; 252/106; 252/DIG. 5;

252/D1G. 13; 252/D1G. 16; 424/245 ANTIBACTERIAL DETERGENT COMPOSITIONS CONTAINING PI-IENYLBISMUTII BlS(2-PYRIDINETHIOL I-OXIDE) CROSS-REFERENCE TO RELATED APPLICATIONS This is a divisional application of my copcnding application Ser. No. 218,584, filed Jan. 17, 1972. for PHENYLBISMUTH BIS(2-PYRID1NETHIOL 1- OXIDE AND COMPOSITIONS CONTAINING SAME, now U.S. Pat. No. 3,753,990, which is turn is a continuation-in-part of my application Ser. No. 98,086, filed Dec. 14, 1970, for PHENYLBISMUTH DI(PYRIDINETHIONE-N-OXIDE) AND COMPOSI- TIONS CONTAINING SAME," now abandoned.

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a new compound, phenylbismuth bis(2-pyridinethiol l-oxide), which can be formed by the reaction between sodium 2- pyridinethiol l-oxide and diphenylbismuth acetate. This invention also relates to the use of this compound, which is highly effective against a broad spectrum of bacteria as well as yeast and fungal species, especially when used on the skin, where the compound is fairly substantive, and to compositions, including detergent compositions, containing said compound.

2. Prior Art Leebricks U.S. Pat. No. 3,239,411, issued Mar. 8, 1966; Gross U.S. Pat. No. 3,197,314 issued July 27, I965; Leebricks Belgian Pat. No. 1.426,l18; and American Cyanamids British Pat. No. 1,003,695 teach that various organo-bismuth compounds, including diphenylbismuth acetate, are effective antibacterial and antifungal agents for use against a wide variety of gram positive and gram-negative organisms. Similarly, the sodium salt of 2-pyridinethiol l-oxide is known. See, e.g., British Pat. No. 761,171, and U.S. Pat. Nos. 2,742,393, and 2,742,476. Schroder et al.s U.S. Pat. No. 3,321,480 teaches triphenyl tin (2-pyridinethione) [triphenyl tin (Z-pyridinethiol 1-oxide)].

SUMMARY OF THE INVENTION Phenylbismuth bis(2-pyridinethiol l-oxide) has the formula:

om G9) Compositions containing phenylbismuth bis(2- pyridinethiol l-oxide) have excellent broad-spectrum antibacterial and anti-fungal action.

Phenylbismuth bis(2-pyridinethiol l-oxide), hereinafter referred to as PBDP, is a yellow powder having a melting point at about 215-2l 8. It is generally insoluble in most common solvents, but is soluble to the extent of about 1% in dimethylsulfoxide, dimethylformamide or dimethylacetamide. The dry solid PBDP is stable and the PBDP appears stable in the presence of soap solutions (pl-I 9-10) and hydrochloric acid (pH Phenylbismuth bis(2-pyridinethiol I-oxide) has been shown to exhibit antibacterial and antifungal effectiveness against, e.g., Gram-positive organisms such as: Brr'i'ibacrerium ammoniagenes, Erysipelotlu'ix [n.rizliosa, Laclulmcillus leiclzmanni, Bacillus subtilus. (lostrizlizmz perfiingens, .S'raplz -'l0c0ccus aureas, Staplrvlvcoct'as' epi- (lermidis, Sart'ina lurca, Streptococcusfavc'alis. ('orynvlmclerlum acnar. Axilla diplillzeroizl No. 16, Oral Sm'plococcas No. 125, Mycobacterium pltlel, Mycohacu'rium smeqmatis, and Mymbacterium hulnei; Gram-negativc organisms such as: Alkaligenes faetalis, Salmmwlla 1yplmsa,. Shigella flarncri, Mima polymorpha, Hera/lea vaginicola, Hemoplzilus gallinarum. Proteus mirahilis, Vibrio nzctscllniltovii, Neissc'ria flai'esc'ens, Escherichia coli, Pscmlomonas ueruginosa, Scrralia martext'cns. Klebsiella pneumoniae, and Enterobacter aerogencs; and Fungi (including yeasts and dermatophytes) such as: Aspergillus niger, Mycrosporum gypseum, Triclmplrrton rubrum, Ticlwphyton interdigilale, Sacclzaromyces (erevisiae, Candida albicans, and Pityrosporum ova/e.

Because of the extremely broad antibacterial and antifungal effectiveness of PBDP it is desirably used as a component of surgical scrub products, bar soaps, shampoos, oral products (e.g., toothpastes, mouthwashes, etc.), first aid sprays. foot powder, deodorants (espe cially underarm deodorants), first aid cream, toilet bowl cleaners, hard surface cleaners, detergents, paints, cosmetics, spermicides, burn dressings, animal feeds, wood preservatives, mildewcides, germicides, algacides, fungicides, medicines, packing preservatives, etc. In extremely small amounts, e.g., 10 ppm., the PBDP will inhibit the growth of a broad variety of organisms. When the PBDP is incorporated in larger amounts, the compositions can be used to destroy organisms, as required. For example, in medicine, both for humans and veterinary medicine, the PBDP can be used to treat a variety of diseases and/or organisms including acne, leprosy, psoriasis, warts, intestinal parasites, dandruff, pseudomonas or coli bacteria, fungus (e.g., athletes foot), vaginal infections, etc. Compositions containing PBDP can be used to treat tissue either to prevent infections or to cure infections.

PBDP is not inactivated by urine or hair oil, but its activity is somewhat diminished by human serum or human red blood cell lysate. Its activity is somewhat greater in acid to neutral media against S. aureus and E. coli. PBDP is substantive to-tooth enamel and cellulose. Thus, PBDP can be used to prevent the growth of plaque in the mouth and can be used against gingivitis. Also, it can be used on bandages, diapers, and sanitary napkins to prevent infections, diaper rash, odor, etc. PBDP can also be used as a slimicide ancl preservative for paper and wood.

PREPARATION OF Pl-IENYLBISMUTH BIS(2-PYRIDINETHIOL l-OXIDE) Phenylbismuth bis(2-pyridinethiol l-oxide) can be prepared by reacting diphenylbismuth acetate with sodium 2-pyridinethiol l-oxide in a 1:1 molar ratio in a solvent such as dimethyl formamide. The compound, a yellow precipitate, can then be filtered and purified as exemplified hereinafter in Example 1. Other reactions to form phenylbismuth bis(2-pyridinethiol I-oxide) include the reaction of sodium, potassium, ammonium, or lithium 2-pyridinethiol l-oxide or any other salt containing a loosely held cation with a phenylbismuth dihalide (e.g., a chloride, bromide, or iodide).

COMPOSITIONS CONTAINING PH ENYLBlSMUTl-l BlS(2-PYRIDINETHIOL l-OXIDE) Phenylbismuth bis(2-pyridinethiol l-oxide) can be used in aqueous and/or non-aqueous solvents to provide antibacterial action. Preferably. the compositions will contain from about 0.2 to about 3% phenylbismuth bis(2-pyridinethiol l-oxide), most preferably from about 1 to about 2%. Desirable compositions are those containing soap and non-soap synthetic detergent compounds. Preferably, the synthetic detergent compounds are cationic, amphoteric, or nonionic.

The term soap" as used herein is meant to designate alkali metal soaps such as the sodium and potassium salts of the higher fatty acids of naturally occurring plant or animal esters, e.g., palm oil, coconut oil, babassu oil, soybean oil, castor oil, tallow, whale and fish oils, grease and lard and mixtures thereof. Sodium and potassium soaps can be made by direct saponification of the fats and oils or by the neutralization of the fatty acids which are prepared in a separate manufacturing process. Examples of suitable soaps are the sodium, potassium, ammonium and alkylolammonium salts of higher fatty acids {C C Particularly useful are the sodium and potassium salts of the mixtures of fatty acids derived from coconut oil and tallow, i.e., sodium or potassium tallow and coconut soap.

Anionic synthetic detergents which can be used with the antibacterial, antifungal, and antiyeast compound of the present invention can be broadly defined as the watersoluble salts, including the alkali metal, ammonium and substituted ammonium salts, or organic sulfuric reaction products having in their molecular structure an alkyl radical containing from about 8 to about 22 carbon atoms and a radical selected from the group consisting of sulfonic acid and sulfuric acid ester radicals.

Important examples of the synthetic detergents which can be used with the compound of the present invention are the following: alkali metal (e.g., sodium and potassium), ammonium and substituted ammonium (e.g., lower alkyl ammonium) salts of the following: alkyl sulfates, especially those obtained by sulfating the higher alcohols produced by reducing the glycerides of tallow or coconut oil; random paraffin sulfonates, in which the alkyl group contains from about 8 to about 22 carbon atoms, prepared by treating random paraffin hydrocarbons in sulfur dioxide and chlorine in the presence of light followed by treating with a base; branched or linear alkyl benzene sulfonates, in which the alkyl group contains from about 8 to about 18 carbon atoms, preferably from about 10 to about 14 carbon atoms, especially those of the types described in U.S. Pat. Nos. 2,220,099, and 2,477,383; sodium alkyl glyceryl ether sulfonates, especially those ethers of the higher alcohols derived from tallow and coconut oil; coconut oil fatty acid monoglyceride sulfates and sulfonates; sulfuric acid esters of the reaction product of one mole of a higher fatty alcohol (e.g., tallow or coconut alcohols) and from about 1 to about 6, preferably about 3 moles of ethylene oxide; alkyl phenol ethylene oxide ether sulfates with about 4 units of ethylene oxide per molecule and in which the alkyl radicals contain about 9 carbon atoms; the reaction product of fatty acids esterified with isethionic acid and neutralized with sodium hydroxide where, for example, the fatty acids are derived from coconut oil; fatty acid amides of the methyl taurine in which the fatty acids, for example, are derived from coconut oil; sulfonated olefins of U.S. Pat. No. 3,332,880; and others known in the art, a number being specifically set forth in U.S. Pat. Nos. 2,486,92l, 2,486,922 and 2,396,278.

The nonionic synthetic detergents which can be used with the antibacterial compound of the present invention may be broadly defined as compounds produced by the condensation of alkylene oxide groups (hydrophilic in nature) with an organic hydrophobic compound which may be aliphatic or alkyl-aromatic in nature. The length of the hydrophilic or polyoxyalkylene radical which is condensed with any particular hydrophobic group can be readily adjusted to yield a watersoluble compound having the desired degree of balance between hydrophilic and hydrophobic elements.

For example, a well-known class of nonionic synthetic detergents is made available on the market under the trade name of Pluronic. These compounds are formed by condensing ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol. The hydrophobic portion of the molecule which, of course, exhibits water insolubility has a molecular weight of from about 1,500 to about 1,800. The addition of polyoxyethylene radicals to this hydrophobic portion tends to increase the water solubility of the molecule as a whole and the liquid character of the products is retained up to the point where polyoxyethylene content is about 50% of the total weight of the condensation product.

Other suitable nonionic synthetic detergents include:

1. The polyethylene oxide condensates of alkyl phenols, e.g., the condensation products of alkyl phenols having an alkyl group containing from about 6 to 12 carbon atoms in either a straight chain or branched chain configuration, with ethylene oxide, the said ethylene oxide being present in amounts equal to 10 to 60 moles of ethylene oxide per mole of alkyl phenol. The alkyl substituent in such compounds may be derived from polymerized propylene, diisobutylene, octane, or nonane, for example.

2. Those derived from the condensation of ethylene oxide with the product resulting from the reaction of propylene oxide and ethylene diamine products which may be varied in composition depending upon.

the balance between the hydrophobic and hydrophilic elements which is desired. For example, compounds containing from about 40 to about polyoxyethylene by weight and having a molecular weight of from about 5,000 to about 11,000 resulting from the reaction of ethylene oxide groups with a hydrophobic base constituted of the reaction product of ethylene diamine and excess propylene oxide, said base having a molecular weight of the order of 2,500 to 3,000, are satisfactory.

3. The condensation product of aliphatic alcohols having from 8 to 18 carbon atoms, in eitherstraight chain or branched chain configuration, with ethylene oxide, e.g., a coconut alcohol ethylene oxide condensate having from 10 to 30 moles of ethylene oxide per mole of coconut alcohol, the coconut alcohol fraction having from 10 to 14 carbon atoms.

4. Long chain tertiary amine oxides corresponding to the following general formula, R R R N 0, wherein R contains an alkyl, alkenyl or monohydroxy alkyl radical of from about 8 to about 18 carbon atoms, from 0 to about 10 ethylene oxide moieties, and from 0 to l glyceryl moiety, and R and R contain from 1 to about 3 carbon atoms and from 0 to about 1 hydroxy group, e.g., methyl, ethyl, propyl, hydroxy ethyl, or hydroxy propyl radicals. The arrow in the formula is a conventional representation of a semi-polar bond. Examples of amine oxides suitable for use in this invention include dimethyldodecylamine oxide, oleyldi(2-hydroxyethyl- ,)amine oxide, dimethyloctylamine oxide, dimethyldecylamine oxide, dimethyltetradecylamine oxide, 3,6- ,9'trioxaheptadecyldiethylamine oxide, di(2-hydroxyethyl)tetradecylamine oxide, 2-dodecoxyethyldime thylamine oxide, 3-dodecoxy-2-hydroxypropyldi(3- hydroxypropyl)amine oxide, dimethylhexadecylamine oxide.

5. Long chain tertiary phosphine oxides corresponding to the following general formula RR'R"P O, wherein R contains an alkyl, alkenyl or monohydroxyalkyl radical ranging from 8 to 18 carbon atoms in chain length, from 0 to about ethylene oxide moieties and from O to l glyceryl moiety and R and R are each alkyl or monohydroxyalkyl groups containing from 1 to 3 carbon atoms. The arrow in the formula is a conventional representation of a semipolar bond. Ex-

amples of suitable phosphine oxides are:

dodecyldimethylphosphine oxide, tetradecyldimethylphospine oxide,

'tetradecylmethylethylphosphine oxide,

3,6,9-trioxaoctadecyldimethylphosphine oxide, cetyldimethylphosphine oxide, 3-dodecoxy-2-hydroxypropyldi( 2-hydroxyethyl)- phosphine oxide,

stearyldimethylphosphine oxide, cetylethylpropylphosphine oxide, oleyldiethylphosphine oxide,

dodecylidiethylphosphine oxide,

tetradecyldiethylphosphine oxide,

dodecyldipropylphosphine oxide, dodecyldi(hydroxymethyl)phosphine oxide, dodecyldi(2"hydroxyethyl)phosphine oxide, tetradecylmethyl-2-hydroxypropylphosphine oxide, oleyldimethylphosphine oxide, 2-hydroxydodecyldimethylphosphine oxide.

6. Long chain dialkyl sulfoxides containing one short chain alkyl or hydroxy alkyl radical of l to about 3 carbon atoms (usually methyl) and one long hydrophobic chain which contains alkyl, alkenyl, hydroxy alkyl, or keto alkyl radicals containing from about 8 to about 20 carbon atoms, from O to about 10 ethylene oxide moieties and from 0 to 1 glyceryl moiety. Examples include:

octadecyl methyl sulfoxide,

Z-ketotridecyl methyl sulfoxide,

3,6,9-trioxaoctadecyl 2-hydroxyethyl sulfoxide,

dodecyl methyl sulfoxide,

oleyl 3-hydroxypropyl sulfoxide,

tetradecyl methyl sulfoxide,

3-methoxytridecyl methyl sulfoxide 3-hydroxytridecyl methyl sulfoxide,

3-hydroxy-4-dodecoxybutyl methyl sulfoxide.

The zwitterionic synthetic detergents useful with the antibacterial agent of the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphonium, and sulfonium compounds, in which the aliphatic radicals can be straight chain or branched. and wherein one of the aliphatic substituents contains from about 8 to 18 carbon atoms and one contains an anionic water solubilizing group, e.g., carboxy,

sulfonate, sulfate, phosphate, or phosphonate. A general formula for these compounds is:

wherein R contains an alkyl, alkenyl, or hydroxy alkyl radical of from about 8 to about 18 carbon atoms, from 0 to about 10 ethylene oxide moieties and from O to l glyceryl moiety; Y is selected from the group consisting of nitrogen, phosphorus, and sulfur atoms; R is an alkyl or monohydroxyalkyl group containing 1 to about 3 carbon atoms; x is 1 when Y is a sulfur atom and 2 when Y is a nitrogen or phosphorus atom; R is an alkylene or hydroxyalkylene of from 1 to about 4 carbon atoms and Z is a radical selected from the group consisting of carboxylate, sulfonate, sulfate, phosphonate, and phosphate groups.

Examples include:

4-[N,N-di(2-hydroxyethyl)-N-octadecylammonio]- butane-l-carboxylate; 5-[S-3-hydroxypropyl-S-hexadecylsulfonio]-3- hydroxypentanel -sulfate;


trioxatetradecoxylphosphonio]-2-hydroxypropane- 1 -phosphate; 3-[N,N-dipropyl-N-3-dodecoxy-2- hydroxypropylammonio]-propane- 1 -phosphonate;

3-( N ,N-dimethyl-N-hexadecylammonio)propane l sulfonate; 3-(N,N-dimethyl-N-hexadecylammonio)-2- hydroxypropanel -sulfonate; 4-[N,N-di(2-hydroxyethyl)-N-(2- hydroxydodecyl)ammonio]-butanel -carboxylate; 3-[S-ethyl-S-(3-dodecoxy-2- hydroxypropyl )sulfonio -propane- 1 -phosphate', 3-[P,P-dimethyl-P-dodecylphosphonio]-propanel phosphonate; and

hexadecylammonio]2-hydroxypentanel -sulfate.

The amphoteric synthetic detergents useful in the present invention can be broadly described as derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. Examples of compounds falling within this definition are sodium 3-dodecylaminopropionate, sodium 3- dodecylaminopropane sulfonate, dodecyl-B-alanine, N-alkyltaurines such as the one prepared by reacting dodecylamine with sodium isethionate according to the teaching of US. Pat. No. 2,658,072, N-higher alkyl aspartic acids such as those produced according to the teaching of US. Pat. No. 2,438,091, and the products sold under the trade name Miranol and described in US. Pat. No. 2,528,378.

Cationic synthetic detergents include those quaternary ammonium, quaternary phosphonium, and ternary sulfonium compounds containing a single straight chain or branched aliphatic radical containing from about 6 to about 20 carbon atoms such as dodecyltrimethylammonium chloride; nonylbenzylethyldimethylammonium nitrate; tetradecylpyridinium bromide; octadecylbutylpropylmethylphosphonium nitrite; decyldimethylsulfonium chloride; etc.

Detergent formulations containing the antibacterial compositions of the present invention can also contain from about to about 90%, preferably from about to about 90% of water-soluble alkaline detergency builder salts, either of the organic or inorganic types. Examples of such builder salts can be found in US. Pat. No. 3,336,233, issued Aug. 15, 1967, column 9, lines 2966, which is incorporated herein by reference. However, at a very high pH, the compound may undergo alkaline hydrolysis and accordingly, for longterm stability, the detergent formulations should have a pH of less than about 10 and preferably the pH should be'approximately neutral. The detergent formulations can also contain any of the usual adjuvants, diluents, and additives, for example, perfumes, anti-tarnishing agents, anti-redeposition agents, dyes, fluorescers, suds builders, suds depressors and the like without detracting from the advantageous properties of the antibacterial compositions of the present invention.

Examples of diluents which may be incorporated into a synthetic detergent bar in amounts of up to about 80% of the bar include soaps, especially alkaline earth metal insoluble soaps, (alkaline earth salts of higher fatty acids); starches such as cornstarch; and clays such as china clay or fullers earth. Other diluents include inorganic salts such as sodium and potassium chlorides and sulfates. Such diluents add bulk to the bar and improve its cosmetic properties without impairing its'detergent or cohesive properties.

The antibacterial and antifungal efficac y of the phenylbismuth bis(2-pyridinethiol l-oxide) is disclosed in the following examples.

EXAMPLE I Preparation of Phenylbismuth bis(2-pyridinethiol l-oxide) 164.7 grams of diphenylbismuth acetate (0.39 moles) were slurried in 2,600 ml. of dimethylformamide. 59.7 grams of sodium 2-pyridinethiol l-oxide (0. 39 mole, 97.3%) were dissolved in 1,300 ml. of dimethylformamide and 18 g. of water were added to this solution. The two solutions were then mixed while stirring at about 32C. The solution turned yellow. The solution was continuously stirred for minutes, and then put on a steam bath for 15 minutes where a temperature of 52C. was attained. The solution was then put on a heating mantle for approximately 1 hour at about 52 58C. The solution was then filtered, and the filtrate separated with dichloromethane and water (a ratio of approximately 121:2). The top layer which contained water and dimethylformamide was discarded. The bottom layer was filtered and washed with water and ether. The resulting impure phenylbismuth bis(2-pyridinethiol l-oxide) was dried in vacuo.

Approximately 350 g. of this phenylbismuth bis(2- pyridinethiol l-oxide) was purified as follows: 30 g. of the crude material was dissolved in 2,000 ml. dimethylacetamide at about 60C. The solution was stirred for' approximately 5 minutes, during which time the phenylbismuth bis(2-pyridinethiol l-oxide) was dissolved, leaving the impurities which were separated by filtering. The filtrate was then diluted with an equal volume of water to precipitate out the phenylbismuth bis(2- pyridinethiol l-oxide). The mixture was cooled in an ice bath to precipitate as much material as possible, and this'material was then separated by filtering. The

residue was washed with water and ether and dried in Calculated Found C 35.7 35.535.3 H 2.4 2.3- 2.2 N 5.2 5.1 (Kjeldahl) Bi 38.8 39.0-39.1 S 11.9 12.0-12.2

EXAMPLE II The phenylbismuth bis(Z-pyridinethiol l-oxide) prepared according to the process of Example I was tested for antibacterial efficacy in the following tests:

I. Minimal Inhibitory Concentration (MIC) in Agar 10,000 ppm. stock solutions of phenylbismuth bis( 2- pyridinethiol l-oxide) were prepared in dimethylformamide (DMF). The active was diluted to the desired test concentration and added to 19-20 ml. of molten trypticase soy agar (TSA) to give a series of graded concentrations (ppm). Thorough rotation of plates assured adequate mixing of the sanitizer before agar solidification. Appropriate control plates containing plain TSA were included. All plates remained at room temperature overnight.

Trypticase soy broth cultures for each test organism (24 hour) were diluted in peptone water to give approximately cells per 0.01 ml. The agar plates, marked in sectors, were inoculated by dropping one drop of each diluted culture from a Kline antigen microdropper onto the appropriate sector of agar. The drops were allowed to dry. The plates were incubated 48 hours at 37C. and then examined for growth. The weakest concentration which completely inhibited growth of an organism was the MIC. The results for the tests were as follows:

Gram-Positive Organisms Staphylococcus aureus (S.a.) Staphylococcus epidermidis (S.ep.) Streptococcus faecalis (St.f.) Streptococcus sp. (St. 126) Sarcina Iuteu (Sar.l.) Diphlheroid sp. (Dip. l6) Brcvibaclerium ammoniagenes En'sipelolhrix insidiosu Lactabacillus leichmanni Bacillus suhtilus C lostridium perfringcns C orynebacterium acnes Axilla diphtheroid No. 16 Oral Streptococcus N0. 126 Mycobaclerium phlei Mycobacterium smegmatis Mycobctclerium balmi Gram-Negative Organisms A 7-day old culture of Corynebac'terium acnes grown anaerobically on brain heart infusion agar plus 1% glucose (Bl-llA 1% G) was washed from the slant withml. of peptone water and drop inoculated on plates containing varying concentrations of phenylbismuth bis(2pyridinethiol l-oxide) in BHlA 1% G. The MIC for this organism was 5 ppm. A similar test was run using Pityrosporum ovale with TSA plus 0.1% of a 95:5 ratio of oleic:palmitic acid as the culture medium. The MIC was 5 ppm.

Fungistatic tests were performed using a modified gradient plate technique reported by Hund and Sandham (Applied Microbiology 17 No. 2:329-30, 1969). Results were as follows: Aspergillus niger 5.8 ppm; Microsporum gypseum 1 ppm.

11. Human Corneum Disc Diffusion Test Cornified epidermis was obtained from the plantar surfaces of human volunteers by cutting sheets of uniform thckness (0.4 mm.) with a dermatome. Discs, 6 mm. in diameter, were cut from the sheets with a No. 2 cork borer. A 1% solution of phenylbismuth bis(2- pyridinethiol l-oxide) was prepared by dissolving the material in DMF to make a 10,000 ppm. stock solution and adding the required amount of this solution to a 2.5% solution of pHisoderm (a commercially available skin cleansing detergent). Twenty ml. of the 1% solution of phenylbismuth bis(2-pyridinethiol l-oxide) in pHisoderm was added to a small screw-cap vial. A control vial was prepared containing ml. of the pHisoderm solution alone. Six skin discs were added to each of the vials which then were mechanically agitated for 10 minutes in a 50C. water bath. The vial contents were transferred to a small beaker where the liquid was removed by suction, and the discs were rinsed three times with ml. of distilled water, each rinse followed by suction removal of the rinse water. The discs were then dried for 2 hours on a paper towel covered with a plexiglass shield to prevent air contamination. The dry discs were placed on the surface of 15 m1. of solidified TSA in a Petri dish (one test disc and one control/dish). A l:l0,000 dilution of each of the six test organisms in TSA at 50C. was prepared. Each Petri dish was overlaid with 10 ml. of agar seeded with oneof the organisms. After agar solidification, the dishes were refrigerated overnight to allow diffusion of any sanitizer away from the disc into the medium. The next day, the dishes were placed in a 37C. incubator for 24 hours. The diameter of any zone which was clear of bacterial growth was measured in mm. These measurements included the 6 mm. diameter disc. A clear zone is indicative of sanitizer retention on the skin after the washing and rinsing process. The results were as follows:

E.c. Psxzi. S.m. l\'.p. F..21.

II 6.5 I L5 13 9 No zones were produced around discs washed in the pHisoderm control solution.

111. Filter Disc Diffusion Test A test which was similar to the skin disc diffusion test was run using filter discs and several types of fabric discs to give an indication of how much sanitizer would remain attached to paper and cloth after rinsing. The results were as follows:

1% phenylbismuth bis(2-pyridinethiol l-oxide) in pHisoderm was used by 12 subjects who washed their hands 4 times. These subjects were chosen at random from a large group of available subjects who use nonsanitizer products exclusively for personal hygiene. The regimented washings in the laboratory followed this procedure: The hands were moistened under 100F. running tap water. The product was squeezed from a plastic bottle into the palm; the amount approximated the size of a 25-cent piece. The product was then distribut'ed over the hands and the lather was worked for 90 seconds. The hands were then rinsed under running tap water for 30 seconds. The four exposures were spread over 2 days, and on the afternoon of the second day, the subjects washed their hands 4 times using a blank bar soap containing no antibacterial agents. A fifth standardized washing was then done in a basin containing 1 liter of sterile distilled water with careful rinsing in this basin. Aliquots were taken from the thoroughly mixed basin contents, added to 30 ml. of sterile distilled water in a membrane funnel, and passed through sterile membrane filters with vacuum suction. The filters were then incubated on pads saturated with 2X concentrated trypticase soy broth plus 10% horse serum and 1% Tween in plastic dishes for 48 hours at 37C. Colonies appearing on the filters were counted and these numbers multiplied by the appropriate dilution factor to determine the number of bacteria/liter in the fifth basin contents. The numbers per basin for each panelist were converted to logarithms to minimize unusually high or low counts. These values were averaged to determine the mean log of the fifth basin bacterial count. Calculation of the log percent reduction for 1 1 l 2 each subject was made using the log of 1.3 X 10 or 6.1 184. an average fifth basin bacterial count obtained from more than 500 handwashings by non-antibacterial Composition No. 4 Percent soap users. These values were averaged to obtain the mean log percent reduction. The results were as fol- 5 Dimethyl coconut iin inc oxide 3,0 lows, Disodium lauryl beta-iminodipropioiiatc 5.0 Sodium coconut sulfate 4.0 Coconut .dicthniiolnniide 1.0 Phenylbismuth bist Z-pyridincthiol l-oxide) l.() Log 71 Reduction Mcnn Log F vlor less than 0.0l 9539 478, I0 Citric acid to ad ust pH to 7.5

Water balance The iilkyl radical is derived from middle cut coconut alcohol and has A second handwashing test in which the subjects iiill following chain length wmimilmn: 0.1 1.2M

t in used a measured amount of product (5 ml.) showed the *Wh lc cut following result:

Composition 5 g A shampoo composition is obtained by uniformly Log Reducllt" M611" Log mixing together the following ingredients:

Composition No. 5

These tests ShOW that hen lbismuth biS( 2- A sham oo composition is obtained bv uniforml mixin to ethcr the p y P f H t Y 2 g o owingir gre icn s: pyn'dmethlol l 0X lde) m g vehlcle ls ff 47 tricthanolamine salt of the sulfated condensation product against normal Skln bacteria in VlVO Under OI'Id UO S of of 3 moles of ethylene oxide and 1 mole of coconut oil fatt 1 2 lhlh' thfll' h'l thd't'ht' 7 actua aco o aving e o owmgc am eng is n u ion: 1

C 66% C 2371 C and 971 C r... skin Disc Drop overlay Test iiiiia'iilzii'iiiiiiifirst?isnziriikisg'iib Skin discs of the type used in the skin disc diffusion Slug??? gfk j g g ia gzt test were washed in various concentrations Of phenyl- 371 monoethanolamide of coconut oil fatty acids having the bismuth bis(2-pyridinethiol l-oxide) in pHisoderm to gagrg 5%? gg? f "g i l-h l'i 18' determine the minimum parts per million of phenylbis- W. Phcnylbismuth bis(2-pyridinethiol l-oxide).

re d i hib' 371 dicthanolamide of coconut oil fatty acids having the muth lms(2 pyndmethlol oxide) qulr It following chain length distribution: 16% C 48% C bacteria seeded and placed directly on the disc. The 1 Cw 9%Cm, and 10% Cm values found were as follows: ethanol.

0.75% methyl cellulose a 2% solution of which has a viscosity of 4000 cps. at 68 F. and a gel point of 140F. 0.7571 perfume. $.11. E.c. Ps.a balance, water.

4O Shampoo formulations containing phenylbismuth bis 2- ridinethiol l-oxide are desirable since the As can be seen from the above date, phenylbismuth i gg dandruff y bis(2-pyridinethiol l-oxide) is an effective antibacterial agent against a wide variety of microorganisms (baete- MPLE IV ria, yeasts, and fungi) and is substantive to skin, paper, I and cloth; Personal Use Detergent Lotion EXAMPLE 1]] Composition No. 6 Percent Potassium coconut glyceryl ether sulfo 3.0 Shampoo Compositions nate (about 23% diglyceryl and the 5() balance substantially all monoglyceryl) Composition No. 1 No. 2 No. 3 Sodium coconut glyceryl ether sulfonate 4.0

(diglyceryl and monoglyceryl content 23 2 as above) P i fziny Sodium tallow glyccryl ether sulfonate 3.0

alcohol sodium salt Sodium curate 87 8] (diglyceryl and monoglyceryl content Sodium alkyl glyceryl & as above); the tallow zt lkyl radicals ether Sulfonmc, 5 5 correspond to those o substantially Sodium acyl Sarcosinmc-g i0 tallow alcohols containing approxiv mately 271 C 327: C and 6071 C Sodium sulfate 0 8 0.8 2.6

. Coconut dimethylamine oxide 5.0 Sodium chloride 6.6 Trisodium hm hate l 2 1 Sodium salt of sulfated condensation 2.0 Diethanolufnidepof 2 0 product of 1 mole of nonylphenol with 4 moles ethylene oxide coconut fatty acids P t m 3 h t l 0 Acetylated lanolin L0 1.0 L0 g pyn -f a t? d ylbismuth bis(2-pyridinethiol l-oxide) 2.0 gg f W2 pyri {-8 Sodium chloride (in addition to 3.0

n l i that from detergents) Sodium toluene sulfonate 2 5 wine 7 7 g l 7 4 Sodium carboxymethylcellulose 0.3 P" (degree of substitution 0.65-0.95;

viscosity of 1% s0ln., 1000-2000 Alky'l radicals derived from fatty alcohol. 25.37: from coconut and 371 from at 250C.) mllow- Acrylamide polymer (contains S-lO mole per- 0.l

-Acyl radicals derived from coconut fatty acids.

cent acrylic acid radicals; monomer is less than 0.05%; viscosity of a 0.5% soln.

EXAMPLE lV-Continued -Continued Personal Use Detergent Lotion Composition Percent Sodium siTEatc (SlO :Na O=2:l) 7,0 Composmo" N 6 Percent 5 Phenylbismuth bis(2-pyridinethiol l-oxide) 3.0

ls about 5 at 25C) Water and minors balance to 100 Salts (sodium and potassium chloride 1-2 and sulfate from detergents) water balance This composition, in addition to performing well in "Coconut indicates alkyl radicals corrcsonding to those ol' niddlc cut coconut fatty its Clea-rung p yv lmparts conslderable antibacte alcohol containing approximately 2% Cm. 667: C 239? C, and 9% CM i l i i to f b i l d i i l i Substantially equivalent results are obtained, i.e., EXAMPLE V good cleaning and good odor reducing properties, when the sodium dodecylbenzene sulfonate of Example Cream Shampoo \/II is replaced, on an equal weight basis, by the followmg: Percent dodecyltrimethylammonium chloride; Sodium coconut glyceryl ether 143 nonylbenzylethyldlmethylarnmonium nitrate;

sulfonate (about 29% diglyceryl tetradecylpyrldrmum bromide; gfg g gg y f subsmmany octadecylbutylpropylmethylphosphonium nitrite; Sodium tallow glyceryl ether sulfonate 2.0 decyldlmethylslllfomum chlonde;

3 3 g y 'y the balance (hexylphenyl)dlmethylbenzylammomum fluoride; su stantia y monog ycery Sodium chloride 7 6'7 elcosyldlmethylbenzylphosphonlum chloride, Sodium sulfate 3.5 coconutalkylmethylmorphohnlum nitrate; N'laumylsarclsinale octadec lmeth lbenz lsulfonium sulfate" Phenylbismuth bis(2-pyridinethiol l-oxide 2.0 25 1 l y M Middle-cut coconut diethanolamine O5 y py l l l c e, Acetylated lanolin L0 laurylpyrldmlum bromide; gf f' g' laurylpyridinium bisulfate;

laurylpyridinium-5-chloro-2-mercaptobenzothiazole; o. 667: u. and 9 7, Cm. laurylpicolinium-p-toluenesulfonate;

tetradecylpyridinium bromide;

l ri chl EXAMPLE v1 PY PF E cetylpyrldrmum bromide; A milled toilet detergent bar is prepared m accorl li i li i b id dance with methods known and used in the art and havlaurylisoquinolinium saccharinate; in the followin corn osition: alk liso uinolinium bromide; g g P y q N-cetyl-N-ethyl-morphol1n1um ethosulfate; benzalkonium chloride; Compmnm" Percent monoquaternaries R N X (one R group is fatty); Sodium alkyl glycerol ether sulfonate 8.0 40 octadecyltrlmetbylammonrum c rl fy g p derivedfmm the l coconut alkyl trrmethylammonlum chloride;

by 03mm" dodecylbenzyltri( octyldecyl)ammonium chloride; Potassium alkyl sulfate (alkyl group 20.0 monoquaternaries R N X (two R groups are fatty);

f fl f? g' gf f g dihexadecyldimethylammonium chloride; 1 l1 383L555; of eoiomlt oil) y di-coconut alkyl dlmethylammomum chloride; Magnesium soap of 80:20 tallow: 1T0 monoquaternarles R N*X' (three R groups are coconut fatty acids fatt Inorganic salts (sodium and potassium 32.0 y a chlorides and sulfates) trl(hydrogenated tallow) methylammomum chloride; Phenylbismuth bisO-pyridinethlol l-oxlde) l.0 distilled tallow amine acetate; water and minors balance to I00 diamine acetates 5O Middlecut alcohols huvinguchuin length distribution substuntiullyas follows: 271 N-oleyl propylene dlamlne monoacetate; sodium tallow alkyl sulfate;

potassium coconut alkyl glyceryl ether sulfonate; Thls b W exhlblts good Q reducmg sodium salt of randomly sulfonated paraffln containproperties evidencing antibacterial effectiveness. It reing an average of 152 Carbon atoms. duces the number of bacteria on the skm significantly. ammonium trideicyl sulfate,

EXAMPLE V11 condensation product of octyl phenol with 15 moles of ethylene oxide per mole of octyl phenol; A granular built synthetic detergent composltlon dimethyldodecylamine oxide; having the following formulation can be prepared and dodecyldimethylphosphine Oxide; the antibacterial compositions of the present invention tetradecyl methyl sulfoxide; can be mcorpmted therein 3-(N,N-dimethyl-N-hexadecylammonio)propane-lsulfonate; 3-dodecylaminopropionate; and Composition Percent dodecyl-B-alanine.

The invention has been described above in COZlJUl'lC- smllum L tion with toilet and laundry detergents. It will be obvi- Sodlum trlpolyphosphate (M) I 40 ous to those skilled in the art, however, that the ant|- Sodium sulfate bacterial compositions of the present invention can also be beneficially employed in such products as shampoos, foot powders, antiseptic ointments, cosmetic products and the like.

A fabric softening composition having the following formulation can be prepared. The antibacterial and antifungal effectiveness of the phenylbismuth bis(2- pyridinethiol l-oxide) is especially desirable since the antibacterial and antifungal compound is extremely substantive to cloth.

Composition Percent Dialkyl dimethylammonium chloride 7 75% active ingredient dispersed in isopropanol and water, the dialkyl groups being approximately 24% hexadecyl, 75% octadecyl and 1% octadecenyl The condensation product of 30 3 moles of ethylene oxide with one mole of coconut alcohol Color and perfume 0.3 Phenylbismuth bis( Z-pyridinethiol l-oxide) 1.0 Water balance Twenty ppm of PBDP were added to a 0.1% aqueous concentratiton of Downy, a commercial cationic softener containing a ditallowalkyl dimethylammonium chloride active. This composition, when used at 27C. for 10 minutes to treat Dacron-prebrightened, Nylon, muslin, Nylon-prebrightened, muslin-prebrightened, and Dacron:cotton (65:35)-prebrightened cloth which had been washed with Ivory Snow, a commercial soap powder, and machine dried, completely controlled the growth of S. Aureus, S. faecalis, E. coli, C. albicans, and P. mirabilis. With similar compositions containing 5 ppm. PBDP, one rinse gave complete protection against S. aureus and S. faecalis, after three rinses E. coli and C. albicans are stopped, and after four rinses, P. mirabilis is inhibited. With similar compositions containing 30-40 ppm. PBDP, one rinse gave protection against P. aeruginosa on muslin, nylon, and the Dacron:cottn blend.

What is claimed is:

1. An antibacterial and antifungal detergent composition comprising:

A. a water-soluble detergent selected from the group consisting of soaps and non-soap synthetic detergents; and

B. from about 0.2 to about 3% of phenylbismuth bis(2-pyridinethiol l-oxide);

said detergent composition having a pH of less than about l0.

2. The antibacterial and antifungal detergent composition of claim 1 wherein the phenylbismuth bis(2- pyridinethiol l-oxide) is present in a concentration of about 1.5%.

3. The antibacterial and antifungal composition of claim 1 in the form of a shampoo consisting essentially of:

A. a water-soluble detergent selected from the group consisting of soaps and non-soap synthetic detergents;

B. from about 0.2 to about 3% of phenylbismuth bis(2-pyridinethiol l-oxide); and

C. balance, water and minors; said shampoo composition having a pH of less than about 10.

4. The antibacterial and antifungal detergent composition of claim 1 in the form of a synthetic antibacterial and antifungal detergent toilet bar consisting essentially of:

A. a water-soluble synthetic detergent;

B. diluents;

C. from about 0.2 to about 3% of phenylbismuth bis(2-pyridinethiol l-oxide); and

D. balance, water and minors.

5. The antibacterial and antifungal detergent composition of claim 1 in the formof an antibacterial and antifungal detergent soap bar consisting essentially of:

A. a metallic salt of a fatty acid of from about 10 to about 20 carbon atoms;

B. from about 0.2 to about 3% of phenylbismuth bis(2-pyridinethiol l-oxide); and

C. balance, water and minors.

6. The antibacterial and antifungal composition of claim 1 containing as an additional ingredient a watersoluble, alkaline detergency builder salt.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3239411 *Jun 14, 1962Mar 8, 1966M & T Chemicals IncOrgano bismuth biocide
US3281366 *Nov 4, 1965Oct 25, 1966Procter & GambleSynergistic antibacterial compositions
US3321480 *Feb 18, 1964May 23, 1967Boehringer Sohn IngelheimTriphenyl-tin-[pyridyl-n-oxide-(2)]-sulfide
US3583999 *Nov 1, 1968Jun 8, 1971Procter & GambleProcess for preparing 2-pyridinethiol n-oxides and derivatives thereof
US3835057 *Oct 6, 1971Sep 10, 1974Lever Brothers LtdAnti-bacterial detergent bar
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4790932 *Dec 3, 1987Dec 13, 1988Henkel Kommanditgesellschaft Auf AktienN-alkyl and N-alkenyl aspartic acids as co-collectors for the flotation of non-sulfidic ores
US5256334 *Feb 28, 1992Oct 26, 1993The Research Foundation Of The State University Of New YorkTriphenylbismuth disoersed in polymer; medical and dental equipment; nonleachable
US5928671 *Jun 26, 1997Jul 27, 1999Winthrop University HospitalMethod and composition for inhibiting bacteria
US6086921 *Oct 28, 1997Jul 11, 2000Wintrop-University HospitalMetal/thiol biocides
US6248371Apr 6, 2000Jun 19, 2001Winthrop University HospitalTuberculosis
US6303101 *Dec 28, 1999Oct 16, 2001Nycomed Imaging AsBismuth compounds
US7531493 *May 22, 2001May 12, 2009The Procter & Gamble CompanyA kit containing a composition for cleaning a fabric article, specifically, a laundry detergent, a fabric conditioner and a fabric treatment composition
US8536399Oct 12, 2010Sep 17, 2013Uni-Charm CorporationMethod of reducing urine odor and article functioning to reduce urine odor
USRE37793Oct 13, 2000Jul 16, 2002Winthrop University HospitalMixture of bismuth compound and dimercaprol
DE3047653A1 *Dec 17, 1980Oct 15, 1981Lion CorpFluessiges wasch- und reinigungsmittel
U.S. Classification514/188, 987/23, 510/131, 510/383, 510/390, 510/382, 510/319, 510/294, 510/133
International ClassificationC11D3/48, A61K8/58, A61Q19/10, A61Q5/02, C07D213/70, C11D3/00, A01N55/02, C07D213/89, C07F9/94
Cooperative ClassificationC11D3/001, A61Q19/10, Y10S514/852, C11D3/48, C07F9/94, A61Q17/005, C07D213/70, A61Q5/02, A61K8/58, C07D213/89
European ClassificationC11D3/48, C07F9/94, C11D3/00B3, A61K8/58, A61Q5/02, A61Q19/10, C07D213/70, C07D213/89