MXPA97009371A - Synergic antimicrobial composition of 2,4,4'-trichloro- 2'-hydroxidiphenyl ether and 1,2-dibromo-2,4-dicianobut - Google Patents

Abstract

The present invention relates to synergistic antimicrobial combinations comprising 2,4,4'-trichloro-2'-hydroxyphenether and 1,2-dibromo-2,4-dicyanobutane. Methods for inhibiting microbial growth using these synergistic antimicrobial combinations are also described

Description

SYNERGIC ANTIMICROBIAL COMPOSITION OF 2,4,4'-TRICLORO- 2'-HYDROXIDIPHENYL ETHER AND 1,2-DIBROMO-2,4-DICIANOBUTANE.

Field of the Invention The present invention relates to antimicrobial, synergistic compositions, which are generally useful for inhibiting microbial growth wherever such microbial growth is found, for example, in aqueous systems related to a wide variety of industrial applications. More particularly, the present invention relates to synergistic mixtures of 2,4,4'-trichloro-2'-hydroxyphenyl ether and 1,2-dibromo-2,4-dicyanobutane. The methods for using them are also described.

BACKGROUND OF THE INVENTION Both 2,4,4'-trichloro-2'-hydroxyphenyl ether, referred to herein as Triclosan, and 1,2-dibromo-2,4-dicyanobutane (DBDCB) are known individually as antimicrobial agents . The unexpected finding of the present invention is that they act synergistically when used in combination. As used herein, the terms "synergistic" and "synergistic" refer to instances where the effectiveness of a composition comprising two or more biocides, such as Triclosan and DBDCB, excethe sum of the efficiencies of the individual components taken in isolation. Therefore, the use of a synergistic biocide combination may allow the use of a lower overall biocide concentration or the performance of an increased antimicrobial effect at a comparable dose. ? The Patents of the U.S.A. Nos. 3,833,731; 3,877,922; 3,873,597; 3,644,380; 3,833,743 and 3,929,858 describe DBDCB and its use as an antimicrobial, antibacterial, fungicidal and algicidal agent. The compounds related to DBDCB are also effective as antimicrobial agents. For example, U.S. Pat. No. 4,442,122 discloses the use of 1,2-dibromo-2-cycloalkane compounds to inhibit microbial growth, and U.S. Pat. Do not. 4,496,581 discloses 1,2-dibromo-2-cyano-2-alkane (heterocyclic) compounds and their uses as antimicrobial agents.

The use of DBDCB and related compounds, in conjunction with other antimicrobial agents is also known in the art. The U.S. Patent Do not.

No. 4,604,405 describes a synergistic antimicrobial composition for industrial and agricultural use, composed of DBDCB and 2,2-dibromo-3-nitroplopropionamide. The U.S. Patent No. 4,655,815 discloses a synergistic antimicrobial mixture comprising DBDCB and a formaldehyde donor. The U.S. Patent No. 4,830,657 describes a synergistic antimicrobial combination comprising DBDCB and 1,2-benzaisothiazoline-3-one. The U.S. Patent No. 5,034,405 discloses the use of mixtures of DBDCB, 2-methyl-4-isothiazolin-3-one and 5-chloro-2-methyl-4-isothiazolin-3-one as antimicrobial agents. The U.S. Patent Do not. ,124,355 describes an antimicrobial composition of DBDCB and 2- (decylitol) ethanoamine and a method for using it. The U.S. Patent No. 5,364,874 discloses a composition containing 2-halo-2-halomethylglutaronitrile and 4,5-polymethylene-4-isothiazolin-3-one, which has antibacterial and fungicidal effects.

Similarly, the use of 2,4,4'-trichloro-2'-hydroxyphenyl ether and related compounds, both alone and in conjunction with other biocides, is known. The synergistic combination of Triclosan and DBDCB, however, has not been described or suggested in the art.

T As used herein, the phrases "antimicrobial", "biocide", and "inhibition of microbial growth" refer to the extermination, inhibition or control of the growth of bacteria, yeasts, mold and / or algae. A large number of important industries have experienced serious and adverse effects arising from the activity of such biological growth in raw materials used in their process waters, in various components of their manufacturing processes, and in the finished products they produce. These industries include paints, wood, textiles, cosmetics and personal care, leather, tobacco, leather, cordage, paper, pulp, plastic, fuels. , of oils, rubber and machinery.

It is contemplated that the synergistic mixture of Triclosan and DBDCB as described herein, as well as the methods for using it, will be useful in virtually any aqueous system or in any article or product of manufacture in which the inhibition of microbial growth is desired, with absence of compatibility problems. Important applications of the synergistic antimicrobial combinations of the present invention include, for example: inhibition of the growth of bacteria and fungi, including yeast and mold, in aqueous paints, adhesives, emulsions, latexes, inks and bonding cements; wood preservation; conservation of oil cuts and working fluids for metals; control of slime-producing bacteria and fungi, including yeast and mold, in pulp and paper mills and in cooling towers; as a bath or spray treatment for textiles and leathers to prevent the growth of mold; as a component of anti-dirt paints to prevent the adhesion of fouling organisms; to protect films from paints, especially exterior paints, from the attack by fungi that occurs during the weathering of the paint film; to protect slime deposits from process equipment during the manufacture of additives for beet and cane sugar, food, food and feed; to prevent the accumulation and deposit of microorganisms in washing and air cleaning systems and in industrial systems for the supply of drinking water; in the control of microbial contamination in water cooling systems with recirculation and closed circuit; in the control of deposits and contamination and microbial in fluids and drilling muds in oil fields, and in processes of secondary oil recovery; in the prevention of bacterial and fungal growth in paper coating processes, which could adversely affect the quality of the paper coating; in the control of growth and bacterial and fungal deposits during the manufacture of various special cardboards, for example, cardboard and particulate cardboard; in the prevention of discoloration by sap stains on freshly cut wood of various species; in the control of bacterial and fungal growth in clay suspensions and pigments, of various kinds and which are manufactured for later use in the manufacture of paint and coatings for paper and which are susceptible to degradation by microorganisms during storage and transport; as a hard surface disinfectant to prevent the growth of bacteria and fungi on walls, floors, etc .; and in swimming pools to prevent the growth of algae.

The synergistic antimicrobial composition described in the present invention is particularly applicable for the control of bacterial and fungal growth in cosmetic and personal care products. Such products include, but are not limited to, creams, lotions, shampoos, conditioners, sunscreens, hand cleaners, liquid hand soaps, detergents, hospital cleaners, bactericidal washes, deodorants, and the like. Cosmetic and personal care products subject to microbial attack may suffer from emulsion separation, discoloration, proliferation of colonies visible to the naked eye, bad smell and pH change; Microbial growth in these products can also lead to potential damage to health.

Accordingly, there remains a real and substantial need for antimicrobial compositions capable of effectively controlling and / or inhibiting microbial growth in industrial aqueous systems and in articles of manufacture. Due to the increase in environmental laws, there is still an additional need to provide biocidal compositions that have an improved antimicrobial effect, which are effective in reducing the doses that have historically been used. The use of smaller quantities of biocides has a favorable impact on the environment and allows users to have significant savings in their costs.

OBJECTIVES OF THE INVENTION The present invention generally satisfies the needs described above by providing antimicrobial, synergistic combinations comprising 2,4,4'-trichloro-2'-hydroxyphenyl ether (Triclosan) and 1, 2- dibromo-2,4-dicyanobutane (DBDCB). The present invention also provides a method for inhibiting microbial growth in aqueous systems and articles of manufacture prone to such growth, which comprises the addition to said systems or application to such articles, of an effective amount of Triclosan and DBDCB.

As used herein, the term "effective amount" refers to the amount of a composition comprising Triclosan and DBDCB, necessary to achieve the desired level of inhibition or control of microbial growth in the aqueous system or in the article being treated. treaty.

Detailed Description of the Invention The present invention is directed to an antimicrobial, synergistic composition, which comprises: a) 2,4,4'-trichloro-2'-hydroxyphenyl ether; and b) 1,2-dibromo-2,4-dicyanobutane, wherein the weight ratio of a) to b), on an active basis, ranges from about 1000: 1 to 1: 1000. The present invention is further directed to a method for inhibiting microbial growth in an aqueous system or in a manufacturing article prone to such growth, which method comprises treating said system or said article with an effective amount of an antimicrobial combination of a 2,4,4'-trichloro-2'-hydroxyphenyl ether; and b) 1,2-dibromo-2,4-dicyanobutane, wherein the weight ratio of a) to b), on an active basis, ranges from about 1000: 1 to 1: 1000.

According to the present invention, the weight ratio of the two components of the synergistic combination is governed by the dose levels for each component demonstrating synergy, based on the 100% active ingredient, in relation to each end-use application. Typically, the weight ratio of components a) Triclosan, and b) DBDCB, ranges from about 1000: 1 to 1: 1000, on an active basis, preferably from about 100: 1 to 1: 500, more preferably from approximately 4: 1 to 1: 64. As will be understood by one skilled in the art, however, the synergistic weight ratio of the two components generally varies to some degree, depending on the application and the organism being controlled. For example, a higher proportion of Triclosan to DBDCB might be more effective in one application, while a higher proportion of DBDCB to Tpclosan might be more effective in another application. The composition of Triclosan / DBDCB against bacteria has been found to be particularly effective when used in a weight ratio of between about 4: 1 and 1:16.

An effective amount of a synergistic combination of Triclosan and DBDCB must be added to the aqueous system being treated. At least 0.1 parts per million (ppm) are added, based on the weight of water in the system being treated, of the synergistic combination described above. Preferably, between about 1 ppm and about 10,000 ppm of Triclosan and between about 10 ppm and 2000 ppm of DBDCB are added, based on the weight of the water in the system being treated. More preferably, between about 50 ppm and about 1,000 ppm of Triclosan and between about 100 ppm and 500 ppm of DBDCB are added, based on the weight of the water in the system being treated. It is within the ordinary knowledge of someone who practices the technique, to determine the effective amount of T biocidal for a given system based on various parameters of the system, including, but not limited to the size of the system, system pH, type of present organisms and the degree of control desired.

Similarly, an effective amount of a synergistic combination of Tpclosan and DBDCB must be applied to the article of manufacture that is being treated. Usually, a solution of the synergistic antimicrobial combination described above and having a concentration of at least 0.1 ppm is incorporated, sprayed, used for bathing, or applied in some other way to the substrate being treated in order to prevent the growth of bacteria, mold, yeast and algae. Again, it is within the ordinary knowledge of one skilled in the art to determine the effective amount of biocide to be applied to a given article of manufacture and that it is being treated.

The active ingredients of the synergistic antimicrobial compositions of the present invention can be used in various formulations: solid, including powders and granulated and finely divided materials; as well as liquids, such as solutions, emulsions, suspensions, concentrates, emulsifiable concentrates, slurries and the like, depending on the intended application and the desired formulation means. In addition, when the synergistic antimicrobial combinations are liquid, they can be used pure or can be incorporated into various formulations, both solid and liquid, and an adsorbate on suitable inert carriers such as talc, clay, diatomaceous earth and the like, or water and various organic liquids such as lower alkanols, kerosene, benzene, toluene, and other petroleum distilled fractions or mixtures thereof. Triclosan is commercially available in powder form from Ciba Geigy, Greensboro, N.C., as Irgasan® DP 300. DBDCB is commercially available from Calgon Corporation, Pittsburgh, PA in various forms, including solid, liquid and aqueous dispersions.

It will also be understood by one skilled in the art that the synergistic antimicrobial combination described herein can be used in combination with other antimicrobial materials. For example, the combination can be combined with other fungicides and bactericides in appropriate concentrations and in the appropriate instances to combine the action of each one to obtain particularly useful results. Such combinations could find particular application in the preparation of germicidal soaps, in the production of cosmetics and aqueous coatings and in the combating of silt accumulations in paper mills.

The synergistic antimicrobial combination of the present invention can be combined with other algicidal agents as well.

According to the present invention there is further provided a method for inhibiting the growth of at least one of: bacteria, yeasts, mold and algae. According to the methods of the present invention, this growth is inhibited in aqueous systems or in articles or manufacturing products prone to such growth. These methods comprise the addition to aqueous systems or the treatment of articles or products containing said bacteria, yeasts, mold and / or algae with an effective amount of a synergistic combination of Triclosan and DBDCB. This addition can be carried out either by the simple incorporation of Triclosan and DBDCB together as a single mixture, or by the addition of the two components separately. Said administration separately can be at the same time or at different times. The net effect will be the same. The system, article or product that is being treated will finally have incorporated or will have applied to it the concentration of the desired dose of each component.

In addition, it is believed that the compositions of the present invention are effective regardless of the method of application. For example, the antimicrobial compositions described herein can be added to a system that is being treated via a continuous feeding practice, a low level semi-continuous feeding practice or through a load feeding. All of these feeding practices will be familiar to someone who has ordinary skills in the art. Load feeding is particularly effective and therefore is a preferred way of employing the methods of the present invention. In a recirculation water system, charge feeding allows the user to monitor the concentration of microorganisms in the system, and to feed product only when the concentrations of microorganisms increase; the user makes savings by feeding an effective amount of Tpclosan and DBDCB only when required. Typically, when a cosmetic or a personal care product is being treated, a batch feed must be added to the product at the end of the manufacturing process, after the product has cooled below about 50 ° C.

As noted above, the present invention is based on the discovery that the use of Triclosan in conjunction with DBDCB produces synergistic results and is effective in controlling the growth of bacteria, yeasts, mold and algae in a variety of industrial and chemical applications. another type. The utility of the synergistic antimicrobial combination described here derives from its versatility both in the many industries in which it can be applied, as well as the numerous microorganisms against which it is effective.

The superior antimicrobial activity of the synergistic antimicrobial combination of Triclosan and DBDCB has been confirmed using standard laboratory techniques. It has been found that the antimicrobial combination is effective, for example, in the inhibition of microbial growth including, but not limited to, the bacteria Klebsiella pneumoniae, Escherichia coli and Pseudomonas aeruginosa, and the yeasts Candida albicans. It is also believed that the combination is effective T against other bacteria, such as Bacillus sp., Staphlococcus sp., Flavobacterium sp., Enterobacter sp. and Xanthomonas sp., anaerobic bacteria, other drinking water organisms such as filamentous bacteria, fungi that include, but are not limited to, several species of Candida and Saccharomyces and white and pink yeasts, and several species of algae.

EXAMPLES The following examples are presented to illustrate the present invention and should not be construed as limiting the invention in any way.

EXAMPLE 1 The biocidal efficacy in microtiter tests of the antimicrobial composition of the present invention is demonstrated below using Pseudomonas aeruginosa, a strain of which was deposited at the American Type Culture Collection (ATCC), 12301 Parkiawn Drive, Rockville, MD, USA under accession number # 15442 of 199. This deposit satisfies the requirements of the Budapest Treaty of the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedures and the Rules therefor.

An 8X standard solution of DBDCB was prepared by dissolving approximately 3. 2 grams (g) of active DBDCB at 20% in about 4 ml of methanol and diluting the volume to about 100 ml with deionized water. The DBDCB used in the examples was obtained from Calgon Corporation, Pittsburgh, PA, as Merguard® 1200. A 4X standard solution of Triclosan was prepared by dissolving about 0.16 g of 99% active Triclosan in about 5 ml of methanol and diluting the volume to approximately 100 ml with deionized water. Triclosan was obtained in Ciba Geigy as Irgasan® DP 300.

Two microtiter plates were prepared for use in the example, each microtiter plate having 8 rows, A-H and 12 columns, 1-12. The amount of each biocide in each well of the plates is described below.

TABLE 1 TI D OF EACH BIOCIDE IN WELLS OF THE FIRST MICROTITULATION PLATE The amount of biocide in each well of the second microtitre plate of each group was as follows: TABLE 2 AMOUNT OF EACH BIOCIDE IN WELLS OF THE SECOND MICROTITULATION PLATE As illustrated in the table above, the amounts of DBDCB and Triclosan were varied in a serial dilution ranging from 800 active ppm to 12.5 ppm active for DBDCB and 400 ppm active at 0.78 for Triclosan.

The minimum inhibitory concentration (MIC) for each biocidal combination was determined against Ps. aeruginosa The MIC is the final amount of biocide required to prevent growth in the well, with growth being defined as turbidity in the medium or a "pellet" of cells that come from the medium and settle to the bottom of the well.

Additional plates were subcultured from the MIC plates at 24 hours after the addition of the biocide. The subculture was done to determine the minimum concentration of biocide (MBC). MBC is the lowest concentration of biocide that results in zero growth after subculture and subsequent incubation.

All of the microtiter plates, including the MIC plates and the MBC plates, were incubated for 24 hours at 37 ° C. After the incubation period of 24 hours, the presence or absence of growth in each well of the plates was determined. Growth of the microtiter plates was determined with a Dynatech MR-5000 microplate reader, available from Dynatech Laboratories, Chantilly, VA, the use of which would be familiar to someone having ordinary skill in the art. The presence or absence of growth in each well, together with the biocide concentration in each well, was then used to determine the synergic properties of the biocidal combinations. The synergistic properties were evaluated by determining the Kull value, or K value. The K value calculation method is well known to those skilled in the art. In this example, the K value was determined by the following formula: T K = GDBDCBI In Combination + fTriclosanl In Combination [DBDCB] Only [Triclosan] Alone wherein "[DBDCB] In Combination" means the concentration of DBDCB which, when used in combination with Triclosan, resulted in the inhibition of microbial growth; "[Tpclosan] In Combination" means the concentration of Triclosan which, when used in combination with DBDCB, resulted in the inhibition of microbial growth; "[DBDCB] Alone" means the concentration of DBDCB that, when used alone, resulted in the inhibition of microbial growth; Y "[Triclosan] Solo" means the concentration of Triclosan which, when used alone, resulted in the inhibition of microbial growth; A K value of less than 1 indicates synergy between the two biocides, a K value of more than 1 indicates antagonism between the two biocides and a K value equal to 1 indicates a summing effect of the two biocides.

The K values determined for Pseudomonas aeruginosa are recorded in Table 3 TABLE 3 VALUES OF "K" OBTAINED FOR PSEUDOMONAS AERUGINOSA As can be seen from the results of Table 3, synergy was demonstrated against Pseudomonas aeruginosa.

EXAMPLE II Example I was repeated with the following differences. The DBDCB was tested at the following concentrations: 200, 100, 50, 25, 12.5, 6.25 and 3.125, with the concentration given in active ppm. The Triclosan standard solution was prepared by dissolving 0.08 g of Irgasan® DP 300, obtained from Ciba Geigy, in approximately 5 ml of methanol and diluting to 100 ml with deionized water. Triclosan was tested at the following concentrations 100, 50, 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39 and 0.195, with the concentrations given in active ppm. The biocidal composition was tested against both the bacteria Pseudomonas aeruginosa (ATCC 15442) and the yeasts Candida albicans, a strain of which was deposited at the American Type Culture Collection (ATCC), 12301 Parkiawn Drive, Rockville, MD, USA. access number # 10231 of 199. This deposit satisfies the requirements of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedures and the Rules therefor. . Bacterial plates were incubated at 35 ° C for 24 hours and yeast plates at 30 ° C for 5 days. The results are presented in Tables 4 and 5 below TABLE 4 VALUES OF "K" OBTAINED FOR PSEUDOMONAS AERUGINOSA TABLE 5 VALUES OF "K" OBTAINED FOR CANDIDA ALB1CANS

Claims (13)

1. Novelty of the Invention 1. A synergistic antimicrobial combination comprising: a) 2,4,4'-trichloro-2'-hydroxyphenyl ether; and b) 1,2-dibromo-2,4-dicyanobutane; wherein the weight ratio of a) to b), in an active base, ranges from about 1000: 1 to 1: 1000.
2. 2. The combination of claim 1, wherein the weight ratio of a) to b) ranges from about 4: 1 to 1: 64.
3. 3. A method for inhibiting microbial growth in an aqueous system, which comprises adding to said system an effective amount of a synergistic antimicrobial combination comprising: a) 2,4,4'-trichloro-2, -hydroxyphenyl ether; and b) 1,2-dibromo-2,4-dicyanobutane; wherein the weight ratio of a) to b), in an active base, ranges from about 1000: 1 to 1: 1000.
4. 4. The method of claim 3, wherein the weight ratio of a) to b), on an active basis, ranges from about 4: 1 to 1: 64.
5. 5. The method of claim 3, wherein the 2,4,4'-trichloro-2'-hydroxyphenyl ether and the 1,2-dibromo-2,4-dicyanobutane are aggregated together as a single composition to the system being treated .
6. 6. The method of claim 3, wherein 2,4,4'-trichloro-2'-hydroxyphenyl ether and 1,2-dibromo-2,4-dicyanobutane are added separately to the system being treated.
7. 7. The method of claim 3, wherein at least 0.1 ppm of the synergistic antimicrobial combination is added to the system being treated.
8. 8. The method of claim 3, wherein between about 50 ppm and 1000 ppm of 2,4,4'-trichloro-2'-hydroxyphenyl ether and between about 100 ppm and 500 ppm of 1,2-dibromo-2,4- dicyanobutane are added to the system that is being treated.
9. 9. A method for inhibiting microbial growth in a manufacturing article, which comprises adding to said article an effective amount of a synergistic antimicrobial combination comprising: a) 2,4,4'-trichloro-2'-hydroxyphenyl ether; and b) 1,2-dibromo-2,4-dicyanobutane; wherein the weight ratio of a) to b), in an active base, varies between (approximately 1000: 1 and 1: 1000.
10. 10. The method of claim 9, wherein the weight ratio of a) to b) ranges from about 4: 1 to 1: 64.
11. 11. The method of claim 9, wherein the 2,4,4'-trichloro-2'-hydroxyphenyl ether and the 1,2-dibromo-2,4-dicyanobutane are aggregated together as a single composition to the article being treated. . ? The method of claim 9, wherein 2,4,4'-trichloro-2'-hydroxyphenyl ether and 1,2-dibromo-2,4-dicyclobutane are added separately to the article being treated. 13. The method of claim 9, wherein said synergistic antimicrobial composition has a concentration of at least 0.1 ppm.