WO2006085859A1 - Biocidal compositions - Google Patents

Biocidal compositions Download PDF

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WO2006085859A1
WO2006085859A1 PCT/US2005/003671 US2005003671W WO2006085859A1 WO 2006085859 A1 WO2006085859 A1 WO 2006085859A1 US 2005003671 W US2005003671 W US 2005003671W WO 2006085859 A1 WO2006085859 A1 WO 2006085859A1
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biocidal
composition
anion
biocidal composition
cation
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PCT/US2005/003671
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French (fr)
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Richard F. Stockel
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Stockel Richard F
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Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
    • A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
    • A01N31/16—Oxygen or sulfur directly attached to an aromatic ring system with two or more oxygen or sulfur atoms directly attached to the same aromatic ring system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
    • A01N47/44—Guanidine; Derivatives thereof

Definitions

  • This invention relates to new biocidal complexes prepared by metathesis synthesis involving either a monomelic or polymeric cationic biocide reacted with the anionic form of a monomelic or polymeric biocide.
  • These complexes tend to have low water solubility therefore for many, but not all applications it is necessary to prepare emulsions or microemulsions to obtain a stable aqueous solution, or the biocidal compositions can be dissolved in an organic solvent.
  • Organic solvents rather than water, can also be utilized in carrying out metathesis reactions provide the starting reactants have some degree of solubility, and the complex product or by-product precipitate from solution as formed to shift the reaction equilibrium to the right.
  • bioactive complexes of this invention can also be synthesized by a straightforward acid-base reaction. This involves the direct combination of a free base bioactive molecule containing at least one or more nitrogen atom having a pair of free electrons with a bioactive molecule capable of donating a proton to form the complexes of this invention.
  • This synthetic route is particularly useful, when preparing complexes of anti-fungal compounds known as azoles and certain amine containing antibiotics having the ability of being protonated respectively.
  • the following reaction serves as an illustration. Chlorhexidine + undecylenic acid chlorhexidium
  • acidic proton transferable molecules include organic phosphoric, phosphonic, phosphinic acids; organic sulfonic or sulfinic acids and the like.
  • the bioactive acid component In order for the acid-base process to work, the bioactive acid component must have a transferable proton to a basic bioactive nitrogen compound having a lone pair of electrons.
  • the reaction is usually conducted in refluxing alcohol (C1-C4), aqueous alcoholic solutions or aprotic dipolar solvents.
  • the effectiveness of individual biologically active compounds can be enhanced by the formation of these complexes as described by this invention.
  • a bioactive cation with a bioactive anion improves the overall biological activity depending on the application.
  • This invention has other important safety and toxicity implications because the resulting complex can be composed of either EPA or FDA approved materials.
  • One parameter, which is important in determining the rate of kill is the dissociation constant of the biocidal complex. Other factors are the ionization and permeability of the complex.
  • U.S. 5,575,993 discloses compositions of polyionenes with anionic biological species.
  • my invention is not anticipated by 993' since the two are significantly different from each other. These differences are clearly delineated in 993 ' whereby only part of the polyionene anion is replaced by a bioactive species, from about 0.005 to about 0.33 or 0.50 degree of substitution depending on the specific polyionene used. All of the resulting compositions are very soluble in water, unlike the compositions of my invention, prior to solubilization with the assistance of surfactants and cosolvents. i he invention will be illustrated by the following examples, which, it will be understood are not intended to be limiting, but merely illustrative.
  • Gemini quats e.g., ethanediyl - ⁇ , w- bis (dodecyldimethyl) ammonium halide
  • Azoles are either triazoles or imidazoles
  • cyproconazole fenbuconazole, tebuconazole, penconazole, tetraconazole
  • Representative cationic monomeric or polymeric biocides included biguanides, guanidines, amidines, quaternaries, polyionenes, phosphoniums, sulfoniums, Gemini quats, amine containing dendrimers, amine containing antibiotics, azoles or any other biocidal cationic moieties.
  • these cationic antimicrobial agents can be other salts besides the hydrochloride.
  • Some examples are hydroxy carboxylic acids, amino acids, sulfonates, and phosphates to name just a few examples.
  • One skilled in organic chemistry could find other suitable substitutes.
  • polymeric species useful for carrying out this invention could be further modified by varying the repeating units or by end capping.
  • U.S. 4,891,423 and 5,741,886 are examples of further enhancing the antimicrobial activities of phmb. Other such examples for different polymeric systems also exist.
  • bioactive anions represent a partial list of actives, which can be utilized in this invention. Knowledgeable persons familiar with biocides can conjure other possible anionics substitutes. In keeping with the spirit of this invention, the list below is illustrative as working examples to achieve very broad antimicrobial activity for a variety of applications.
  • the preferred surfactants which form microemulsions or emulsions with the compositions of this invention, are by and large, either of the amphoteric and non-ionic type, or combinations thereof.
  • Highly charged anionic surfactants have the potential to reduce the overall bioactivity of these complexes by causing some degree of precipitation, thereby lessening its effective.
  • amphoteric Surfactants that carry a positive charge in strongly acidic media, carry a negative charge in strongly basic media, and form zwitterionic species at intermediate pH's are amphoteric.
  • the preferred pH range for the stability and effectiveness is from about 5.0 to about 9.0. Under this pH range the amphoteric surfactant is mostly or fully in the zwitter (overall neutral charge) form, therby negating any dilution of bioactivity of the compositions of this invention.
  • amphoteric surfactants useful for preparing microemulsions or emulsions for the complexes of this invention. These are:
  • Nonionic surfactants have also been found to be useful to form small particle micelles for these complexes. These can be classified as the following:
  • alkanolamides a. alkanolamides b. ethoxylated (propoxylated) amides
  • esters a. ethoxylated (propoxylated) carboxylic acids b. ethoxylated (propoxylated) glycerides c. glycol esters (and derivatives) d. mono (di) glycerides e. polyglycerol esterts f. polyhydric alcohol esters and ethers g. sorbitan / sorbital esters h. di (tri) esters of phosphoric acid
  • Ethers a. ethoxylated (propoxylated) alcohol b. ethoxylated (propoxylated) lanolin c. ethoxylated (propoxylated) polysiloxanes d. ethoxylated-propoxylated block copolymers
  • Two suitable cationic surfactants include D,L-2-pyrrolidone-5-carboxylic acid salt of ethyl-N-cocoyl-L-arginate (CAE), marketed by Ajinomto and cocamidopropyl, cocamidopropyl PG dimonium chloride phosphate (PTC), marketed by Uniqema, and the like.
  • CAE ethyl-N-cocoyl-L-arginate
  • PTC cocamidopropyl PG dimonium chloride phosphate
  • an effective surfactant system will differ to some degree for each biocidal complex.
  • the choice will depend on the surfactants hydrophilic- lipophilic balance (HLB) to form a stable small particle micelle in an aqueous or aqueous cosolvent medium solution.
  • HLB hydrophilic- lipophilic balance
  • the combination of two or more amphoteric or a amphoteric-nonionic system or two or more nonionic surfactants can also be utilized to achieve satisfactory results.
  • an appropriate solvent is required to solublize the biocidal composition in order to form an emulsion, or a microemulsion.
  • the latter usually needs a cosolvent.
  • the concentration of water is about or greater than 70 weight percent of the total solvents present. It is also preferable to have at least 10 weight percent or greater of actives present in the concentrate.
  • aprotic dipolar solvent in part, or in toto.
  • these types of solvents are dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidone, gamma butylrolactone, morpholine N-oxide, or dimethyl-2-piperidone and the like.
  • Other useful solvents found are mono/di/tri phosphates or mixtures thereof.
  • the complex has considerable hydrophobic functionality e.g., stearates it may be necessary to use aromatic solvents like toluene or xylene in part or in toto.
  • aromatic solvents like toluene or xylene in part or in toto.
  • the total amounts of any of the solvents in preparing microemulsions should be kept to a minimum.
  • About 30 weight percent of the concentrate represents the upper limit. With 10 weight percent or more preferred. These percentages are based only on the total weight of all the solvents present in the concentrate including water.
  • a second criteria for the selection of a water-solvent system for these complexes is dependent on the specific application. If the intended use is for human or animal applications then the solvents should have a safe toxicity/irritation profile.
  • Bioactive molecules are produced using the ultimate green chemistry approach.
  • Water is the solvent of choice, by-products are harmless salts and yields are excellent to quantitative.
  • the reactants are only slightly soluble in water, alcohols or other solvents can be used if the product precipitates from solution.
  • the appropriate cationic moiety is reacted with the desired anionic moiety in water.
  • concentration of reactants can vary from 20 to about 60 weight percent of the total solution. The reaction takes place at room temperature, and is generally completed within one hour. However, it should be noted that metathesis reactions can be successfully carried out in non-aqueous solvents as well.
  • the final product is readily removed by decantation, dried in an oven, and generally can be used as is certain applications.
  • the acid component In order for the acid-base synthesis to give good yields, the acid component must have a transferable proton (pka) to a basic molecule (pkb).
  • the reaction is usually conducted in refluxing from 1 to 10 hours in alcohol (C 1 -C 4 ) or aqueous alcoholic solutions.
  • the product is isolated after evaporating off the solvent(s). Recrystallization or chromatographic purification is preferred, if necessary.
  • the complex is dissolved in the minimum amount of a solvent with the appropriate Hildebrand solubility parameter.
  • the solubility parameter is a numerical value that indicates the relative solvency behavior of a specific solvent.
  • Hildebrand solubility parameters from about 8.5 to about 22.0 are suitable for solubilization of the complexes of this invention.
  • the correct solvent for solubilization will be on the low side, if the bonding has more co valency, and if the boding is more ionic, then the proper solvent will have a much higher value.
  • Combinations of solvents are also useful in preparing emulsions or microemulsions.
  • amphoteric or non-ionic is added to the dissolved complex.
  • Combinations of the above type surfactants can also be utilized.
  • the complex-solvent-surfactant is then diluted with water to the active concentration required for the particular application to form an emulsion or microemulsion depending on the micellar size and choice of solvents / cosolvents.
  • the bacteriostatic activity of several complexes was investigated by testing at 0.1 weight percent using Oxioid No. 2 nutrient broth and inoculating the broth with 1 ml of a 24 hour broth culture of the test organisms after incubation at the optimum growth temperature of the organism for 48 hours.
  • Dolvionene 6.6-triclosan polyionene 6.6 is prepared from tetramethyl hexamethylenediamine and 1 ,6-dichloro-hyxamethylene.

Abstract

Biocidal compositions formed by metathesis of either monomeric or polymeric bioactive cations with either monomeric or polymeric bioactive anions to form essentially water insoluble complexes. These novel and unique compounds or polymers are effective against a wide variety of microbial species.

Description

Biocidal Compositions
Invention
This invention relates to new biocidal complexes prepared by metathesis synthesis involving either a monomelic or polymeric cationic biocide reacted with the anionic form of a monomelic or polymeric biocide. These complexes tend to have low water solubility therefore for many, but not all applications it is necessary to prepare emulsions or microemulsions to obtain a stable aqueous solution, or the biocidal compositions can be dissolved in an organic solvent.
The formation of all the complexes of this invention can usually be synthesized by metathesis reactions carried out in aqueous solutions, or aqueous alcohol mixtures. These bioactive complexes are produced using an environmental approach (green chemistry). Water is the solvent of choice, by-products are harmless salts and yields are excellent.
Organic solvents, rather than water, can also be utilized in carrying out metathesis reactions provide the starting reactants have some degree of solubility, and the complex product or by-product precipitate from solution as formed to shift the reaction equilibrium to the right.
Some of the same bioactive complexes of this invention can also be synthesized by a straightforward acid-base reaction. This involves the direct combination of a free base bioactive molecule containing at least one or more nitrogen atom having a pair of free electrons with a bioactive molecule capable of donating a proton to form the complexes of this invention. This synthetic route is particularly useful, when preparing complexes of anti-fungal compounds known as azoles and certain amine containing antibiotics having the ability of being protonated respectively. The following reaction serves as an illustration. Chlorhexidine + undecylenic acid chlorhexidium
Base acid undecylenate complex
Other acidic proton transferable molecules include organic phosphoric, phosphonic, phosphinic acids; organic sulfonic or sulfinic acids and the like.
In order for the acid-base process to work, the bioactive acid component must have a transferable proton to a basic bioactive nitrogen compound having a lone pair of electrons. The reaction is usually conducted in refluxing alcohol (C1-C4), aqueous alcoholic solutions or aprotic dipolar solvents.
These complexes are very effective biocides against a variety of bacteria, fungi, protozoa, helminthes and viruses.
Background of the Invention
Individually, the biocides of this invention are well known in the published literature, however the complexes of this invention are quite unique, novel and represent new biocidal compositions.
In accordance with this invention, the effectiveness of individual biologically active compounds can be enhanced by the formation of these complexes as described by this invention. Thus the combination of a bioactive cation with a bioactive anion improves the overall biological activity depending on the application. Specific applications where a sustain release of a biocidal molecule over time is beneficial, rather than an immediate quick kill, are wood preservatives, dermatological treatment, paint in-can preservatives, coatings, and dental applications to mention a few. This invention has other important safety and toxicity implications because the resulting complex can be composed of either EPA or FDA approved materials.
Another advantage involves the green chemistry used in synthesizing most of these compositions. Fortunately, the metathesis reaction can be carried out in a totally aqueous medium. The by-product of this reaction is a salt, which does not represent any serious environmental problem for disposal. In fact, many salts can be recycled for other uses.
One parameter, which is important in determining the rate of kill is the dissociation constant of the biocidal complex. Other factors are the ionization and permeability of the complex.
While the literature is replete with many patents and articles concerning the individual components of this invention, there is scarce mention of preparing the complexes of this invention. For example, WO97/25085 describes the combination (admixture) of chlorhexidine with triclosan to contribute antimicrobial activity when applied to medical devices and the like. The inventors do not anticipate our technology, because no mention is made about a chemical reaction between these two biocides, nor does the method they use to apply these biocides allow the formation of a complex.
U.S. 5,575,993 discloses compositions of polyionenes with anionic biological species. However, my invention is not anticipated by 993' since the two are significantly different from each other. These differences are clearly delineated in 993 ' whereby only part of the polyionene anion is replaced by a bioactive species, from about 0.005 to about 0.33 or 0.50 degree of substitution depending on the specific polyionene used. All of the resulting compositions are very soluble in water, unlike the compositions of my invention, prior to solubilization with the assistance of surfactants and cosolvents. i he invention will be illustrated by the following examples, which, it will be understood are not intended to be limiting, but merely illustrative.
List of Bioactive Cationic Agents
The following specific monomelic and polymeric bioactive cationic agents are illustrative of this invention. They by no means represent all possible cationic biocides, but instead are examples of the broad array available to a practitioner who wishes to carry out the scope of this invention.
Examples:
• Polyhexamethylene biguanide hydrochloride salt
• Polyhexamethylene guanidine hydrochloride salt
• Dimethyldidecyl ammonium chloride
• Benzalkonium chloride
• Bemzethonium chloride
• Chlorhexidine digluconate
• Poly (dimethyl butenyl ammonium chloride) alpha, omega-bis (triethanol- ammonium chloride
• Propamidine
• Dibromopropamidine
• Poly (oxyethylene) (dimethylimino) ethylene (dimethylimino) ethylene dichloride
• Dequalinium chloride
• Polyquaternium 2
• Hexetidine
• Cetyl pyridinium chloride
• Tetrakis (hydroxy methyl) phosphonium sulfate
• Gemini quats, e.g., ethanediyl - α, w- bis (dodecyldimethyl) ammonium halide
• Quaternary ammonium dendrimeric biocides (U.S. 6,440,405)
• Long chain sulfonium salts
• Long chain phosphonium salts
• Antibiotics containing at least one amine salt or more e.g., tetracycline, doxycycline, minocycline and the like
• Azoles (are either triazoles or imidazoles) e.g., cyproconazole, fenbuconazole, tebuconazole, penconazole, tetraconazole are some examples
• Polyaminosaccharide salts like chitosan hydrochloride
• Cationic polypeptides
Representative cationic monomeric or polymeric biocides included biguanides, guanidines, amidines, quaternaries, polyionenes, phosphoniums, sulfoniums, Gemini quats, amine containing dendrimers, amine containing antibiotics, azoles or any other biocidal cationic moieties.
It is understood that these cationic antimicrobial agents can be other salts besides the hydrochloride. Some examples are hydroxy carboxylic acids, amino acids, sulfonates, and phosphates to name just a few examples. One skilled in organic chemistry could find other suitable substitutes.
The specific biocides described are illustrative of this invention, but do not present a complete inventory of all the possible combinations possible. Anyone skilled in the art of chemistry and biology can conceptualize other modifications. In particular, some of the
polymeric species useful for carrying out this invention could be further modified by varying the repeating units or by end capping. U.S. 4,891,423 and 5,741,886 are examples of further enhancing the antimicrobial activities of phmb. Other such examples for different polymeric systems also exist.
List of Specific Bioactive Anionic Agents
The following specific monomelic and polymeric bioactive anions represent a partial list of actives, which can be utilized in this invention. Knowledgeable persons familiar with biocides can conjure other possible anionics substitutes. In keeping with the spirit of this invention, the list below is illustrative as working examples to achieve very broad antimicrobial activity for a variety of applications.
• Sodium hydroxymethyl glyconate
• Sodium tetrathiocarbonate
• Sodium tribromosalicylanilide
• Sodium tribromophenol
• Sodium 2-bromo-4-hydroxy acetophenone
• Disodium cyanodithioimidocarbamate
• Potassium N-hydroxymethyl dithiocarbamate
• Sodium allyl paraben
• Sodium salicylanilide
• Sodium salicylate
• Sodium hexylresorcinol
• Hydroxyl carboxylic acid salts e.g., sodium lactate
• Sodium omadine • Disodium bithional
• Sodium trichloroacetate
• Sodium stearate
• Sodium mercaptobenozthiazole
• Sodium dithiodimethyl carbamate
• Sodium stearate
• Sodium mercaptobenozthiazole
• Sodium dithiodimethyl carbamate
• Sodium undecylenic aid
• Sodium ortho-phenylphenol
• Dissodium hexachlorophene
• Sodium triclosan
• Sodium 2,6-di-t-butyl, 4-methyl phenol
• Sodium tetraborate
• Poly anionic compositons like polydivinyl ether-maleic anhydride alternating copolymer
• Anionic dendrimers (U.S. 6,464,971)
• Chitosan derivatives having carboxylate, sulfate, sulfonate, phosphonate or phosphate anions
• EDTA and derivatives having carboxylate anions
• 1 -hydroxy ethane- 1, 1-diphosphonic acid
• nitrilotris (methylenephosphonic acid)
• ethylenediaminetetrakis (methylene-phosphonic acid)
• mono or di alkyl phosphates or mixtures thereof
• l-hydroxy-2-(3-pyridinyl)-ethylidine-l,l-bisphosphonic acid, mono sodium salt
• Anionic polypeptides Surfactants
Experimentally, it has been determined that the preferred surfactants, which form microemulsions or emulsions with the compositions of this invention, are by and large, either of the amphoteric and non-ionic type, or combinations thereof. Highly charged anionic surfactants have the potential to reduce the overall bioactivity of these complexes by causing some degree of precipitation, thereby lessening its effective.
It was also found that certain cationic surfactants, sometimes in combination with nonionic and/or amphoteric surfactants are effective in forming stable emulsions and/or microemulsions.
Surfactants that carry a positive charge in strongly acidic media, carry a negative charge in strongly basic media, and form zwitterionic species at intermediate pH's are amphoteric. The preferred pH range for the stability and effectiveness is from about 5.0 to about 9.0. Under this pH range the amphoteric surfactant is mostly or fully in the zwitter (overall neutral charge) form, therby negating any dilution of bioactivity of the compositions of this invention.
There are several classes of amphoteric surfactants useful for preparing microemulsions or emulsions for the complexes of this invention. These are:
1. N-alkylamino acids
2. alkyldimethyl betaines
3. alkylamino betaines
4. sulfobetaines
5. imidazolines
6. amino or imino propionates Some of the above amphoteric surfactants have moderate to good antimicrobial activity against certain microorganism, and hence can be synergistic with the bioactive compositions of this invention.
Nonionic surfactants have also been found to be useful to form small particle micelles for these complexes. These can be classified as the following:
1. alcohols
2. alkanolamides a. alkanolamides b. ethoxylated (propoxylated) amides
3. Amine oxides
4. .-. Esters a. ethoxylated (propoxylated) carboxylic acids b. ethoxylated (propoxylated) glycerides c. glycol esters (and derivatives) d. mono (di) glycerides e. polyglycerol esterts f. polyhydric alcohol esters and ethers g. sorbitan / sorbital esters h. di (tri) esters of phosphoric acid
5. Ethers a. ethoxylated (propoxylated) alcohol b. ethoxylated (propoxylated) lanolin c. ethoxylated (propoxylated) polysiloxanes d. ethoxylated-propoxylated block copolymers
Two suitable cationic surfactants include D,L-2-pyrrolidone-5-carboxylic acid salt of ethyl-N-cocoyl-L-arginate (CAE), marketed by Ajinomto and cocamidopropyl, cocamidopropyl PG dimonium chloride phosphate (PTC), marketed by Uniqema, and the like.
It has been observed that the choice of an effective surfactant system will differ to some degree for each biocidal complex. The choice will depend on the surfactants hydrophilic- lipophilic balance (HLB) to form a stable small particle micelle in an aqueous or aqueous cosolvent medium solution. Also the combination of two or more amphoteric or a amphoteric-nonionic system or two or more nonionic surfactants can also be utilized to achieve satisfactory results.
It has been found that effective concentrations (based on the weight of the complex) or surfactants are in the range of 0.4 weight percent to about 6.0 weight present.
Solvents
Since the complexes are slightly soluble or insoluble in water, an appropriate solvent is required to solublize the biocidal composition in order to form an emulsion, or a microemulsion. The latter usually needs a cosolvent.
The choice of a solvent to effectively dissolve the complex is dependent on at least tow criteria for the purpose of this invention.
In the concentrate form before dilution with additional water for a specific application, it is highly desirable that the concentration of water is about or greater than 70 weight percent of the total solvents present. It is also preferable to have at least 10 weight percent or greater of actives present in the concentrate.
In order to accomplish these desirable levels of solvents and actives, it is incumbent to choose the proper solvents. This can be done by determining the solubility parameter of the complex.
Experimentally, it has been found that when the complex has considerable ionic character and only slightly soluble in water, than alcohols (C1-C4), glycols, glycol ethers, glycol esters, di, tri and poly hydroxylic solvents can be utilized.
When the complex has a predominance of covalent bonding, then it may be necessary to use aprotic dipolar solvent in part, or in toto. Examples of these types of solvents (not all inclusive) are dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidone, gamma butylrolactone, morpholine N-oxide, or dimethyl-2-piperidone and the like. Other useful solvents found are mono/di/tri phosphates or mixtures thereof.
In certain cases whereby the complex has considerable hydrophobic functionality e.g., stearates it may be necessary to use aromatic solvents like toluene or xylene in part or in toto.
Sometimes, it was found necessary to use combinations of the above solvents to achieve stable emulsions or microemulsions for the biocidal complexes of this invention.
In the final analysis, the total amounts of any of the solvents in preparing microemulsions should be kept to a minimum. About 30 weight percent of the concentrate represents the upper limit. With 10 weight percent or more preferred. These percentages are based only on the total weight of all the solvents present in the concentrate including water.
A second criteria for the selection of a water-solvent system for these complexes is dependent on the specific application. If the intended use is for human or animal applications then the solvents should have a safe toxicity/irritation profile.
If the end-use is an industrial application, then the choice of solvents is much broader, but still should be relatively safe.
General Synthesis for the Formation of the Complexes of this Invention
The formation of all the candidate molecules are synthesized by straight forward metathesis reactions carried out in aqueous solutions, where the starting reactants are both water-soluble and the resulting complex is unsoluble or sparingly soluble in water.
These bioactive molecules are produced using the ultimate green chemistry approach. Water is the solvent of choice, by-products are harmless salts and yields are excellent to quantitative. Therein one or both of the reactants are only slightly soluble in water, alcohols or other solvents can be used if the product precipitates from solution.
The appropriate cationic moiety is reacted with the desired anionic moiety in water. The concentration of reactants can vary from 20 to about 60 weight percent of the total solution. The reaction takes place at room temperature, and is generally completed within one hour. However, it should be noted that metathesis reactions can be successfully carried out in non-aqueous solvents as well.
The final product is readily removed by decantation, dried in an oven, and generally can be used as is certain applications.
Acid-Base Procedure
This well known facile reaction can be utilized in some cases by the reaction of a conjugate base (free base) of a biocidal cation with the conjugate acid (protonated) of the biocidal anion. This can be represented by the following example:
Figure imgf000014_0001
In order for the acid-base synthesis to give good yields, the acid component must have a transferable proton (pka) to a basic molecule (pkb). The reaction is usually conducted in refluxing from 1 to 10 hours in alcohol (C1-C4) or aqueous alcoholic solutions. The product is isolated after evaporating off the solvent(s). Recrystallization or chromatographic purification is preferred, if necessary.
It has been found that the acid-base reaction is advantageous but not limiting for the formation of complexes involving amine containing antifungal azoles and antibiotics when reacting them with antimicrobial agents capable of donating a proton.
General Method for the Formation of EmulsionsZMicroeniulsions for the Complexes of this Invention
The complex is dissolved in the minimum amount of a solvent with the appropriate Hildebrand solubility parameter. The solubility parameter is a numerical value that indicates the relative solvency behavior of a specific solvent. Hildebrand solubility parameters from about 8.5 to about 22.0 are suitable for solubilization of the complexes of this invention.
Depending on the ionic/covalent bonding energies of these compositions, the correct solvent for solubilization will be on the low side, if the bonding has more co valency, and if the boding is more ionic, then the proper solvent will have a much higher value.
Combinations of solvents are also useful in preparing emulsions or microemulsions.
Next, an amphoteric or non-ionic is added to the dissolved complex. Combinations of the above type surfactants can also be utilized.
The complex-solvent-surfactant is then diluted with water to the active concentration required for the particular application to form an emulsion or microemulsion depending on the micellar size and choice of solvents / cosolvents.
Examples - Solubilization of Complexes Dilutable with Water
1. phmb triclosante
20g active
20Og methanol
1.5g Tego Betaine Z (real)
2. didecyldimethyl ammonium 2-mercapto-benzothiazole
20g active
19.41 wt. % 20Og isopropanol solids 3.0g Tego Betaine (real)
3. chlorhexidinium di (triclosanate)
20g active
20.20 wt. % 150g ethanol solids 2g each Tween 20/Tego Betaine Z (real)
Microbiological Tests
The bacteriostatic activity of several complexes was investigated by testing at 0.1 weight percent using Oxioid No. 2 nutrient broth and inoculating the broth with 1 ml of a 24 hour broth culture of the test organisms after incubation at the optimum growth temperature of the organism for 48 hours.
The organisms tested were:
Staphylococcus aureous (gram positive) Pseudononas aeruginosa (gram negative) Escherichia coli (gram negative)
Compounds 2,5,6,7,8,9 and 10 were tested and found to be bacteriostatic at 0.1 weight percent against the above 3 organisms. MIC Tests - Data is Reported in ppm
Strains Compositions
JL .2.
Bacillus cereus 4342 >5 >5 >5
MRSA 12064 >2 >2 >2
Streptocci 12235 5 5 5
Enterococcus faecalis 3 >2 5
Enterobacter 12315 >2 >2 >2
Shigella 12440 >2 >2 >2
MRSA 12060 >2 >2 >2
Klebsiella 12261 >2 >4 >4
Bacillus subtilis 11590 >2 >2 >2
Staph, epϊdermidis 12950 >2 >2 >5
Staph, epidermidis 12964 >2 >5 >2
Candida glabrate 90030 >2 >2 >2
Cryptococcus neoformans CNH 99 >2 >2 >2
Candida krusci 6258 >5 >2 3
Candida albicans 5108 > 2 2
1. chlorhexidene-triclosan
2. pentamidine-triclosan
3. Dolvionene 6.6-triclosan polyionene 6.6 is prepared from tetramethyl hexamethylenediamine and 1 ,6-dichloro-hyxamethylene.

Claims

Claims:
1 Biocidal compositions prepared by a methathesis reaction of a water-soluble m onomeric or polymeric biocidal cationic molecule with a water-soluble monomeric or polymenc biocidal anionic molecule.
2 A biocidal composition as described in claim 1 comprising a biguanide cation.
3. A biocidal composition as described in Claim 2 wherein the biguanide cation is derived from chlorhexidine.
4 A biocidal composition as described in Claim 2 wherein the biguanide cation is derived from polyhexamethylene biguanide.
5. A biocidal composition as described in Claim 1 comprising a guanidine cation.
6 A. biocidal composition as described in Claim 5 wherein the guanidine cation
7. A biocidal composition as described in Claim 5 wherein the guanidine cation is derived from polyhexamethylene guanidine.
8 A. composition as described in Claim 1 comprising an amidine cation
9. A biocidal composition as described in Claim 8 wherein the amidine cation is derived from dibrommopropanidine.
10. A composition as described in Claim 1 comprising a polyionene cation
11. A biocidal composition as described in Claim 10 wherein the polyionene cation is po!y (oxyethlene (dimethylimino) ethylene (dimethylimino ethylene).
12 A composition as described in Claim 1 comprising a biocidal quaternary cation.
13. A biocidal composition as described in Claim 12 wherein the quaternary is didecyldimethyi ammonium cation.
14. A compositϊon as described in Claim 1 comprising a phosphonium cation.
15. A biocidal composition as described in Claim 14 wherein the phosphonium cation is Tetrakis (hydroxymethyl) phosphomium cation.
16. A composition as described in Claim 1 comprising a biocidal amine containing antibiotic acid salt.
17. A biocidal composition as described in Claim 16 wherein the amine containing antibiotic is a tetracycline, clindamycin, tazaroteme, erythromycin, clinafioxacin, doxycycline, minocycline, or lincomycin acid salt.
18 A composition as described in Claim 1 comprising a biocidal azote antifungal acid salt
19. A biocidal composition as described in Claim 18 wherein the azole is a cloconazole, clotrimazole, cyproconazole, fenbuconazole. myclobutanil, propiconazole, tebuconazole, triodinefon, miconazole, or flucytosine acid salt.
20. A biocidal composition as described in Claim 1 comprising a phenolate or substituted phenolate anion.
21. A biocidal composition as described in Claim 20 wherein the phenolate anion is triclosan anion.
22. A biocidal composition as described in Claim 20 wherein the phenolate anion has a Cg-C22 alkyl group.
23. A biocidal composition as described in Claim. 1 comprising a flavonoid anion.
24. A biocidal composition as described in Claim 23 wherein the flavonoid anion ns hesperfiπ.
25. A biocidal composition as described in Claim 1 comprising an organomercapto anion
6. A biocidal composition as described in Claim 25 wherein the organomercapto anion is 2-mercapto-pyridine-N-oxide.
27. A biocidal composition as described in Claim 1 comprising a dialkyl dithiocarbamate anion.
28. A biocidal composition as described in Claim 27 wherein the dialkyl dithiocarbamate anion is dimethyl diihiøcarbamate.
29. A biocidaJ composition as described in Claim 1 comprising an enolizable hydrogen atom.
30. A biocidal composition as described in Claim 29 wherein the enolizable hydrogen atom anion molecule is hinokitiol.
31. A biocidal composition as described in Claim 1 comprising mono, di alkyl phosphate, or mixtures thereof.
32. A biocidal composition as described in Claim 31 wherein the mono or di phosphate anion is ethyl hexiyl phosphate.
33. A biocidal composition as described in Claim 1 comprising a carboxylic anion.
34. A biocidal composition as described in Claim 33 wherein the carboxylic anion is undecylenic acid.
35. A biocidal composition as-described in Claim 1 comprising an aminocarboxylic anion.
36. A biocidal composition as-described in Claim 35 wherein the aminocarboxylic acid anion is ethylenediamine tetra-acetic acid.
37. A biocidal composition as described in Claim 1 comprising an aminophosphonate.
38. A Biocidal composition as described rn Claim 37 wherein the aminophosphonate is ethylenediamine tetra (methylphosphonic acid).
39. The compositions of Claim 1 solubilized in form of an emulsion by dissolving the complex in a solvent, which also contains a surfactant capable of forming actable micellar solution when diluted with water.
40. The solubϊized composition of Claim 39 wherein the solvent is lower aϊkyϊ alcohol from CL to Gi.
4L The solubilized composition of Claim 39 wherein the solvent is a glycøi.
42. The solubilized composition of Claim 39 wherein the solvent is glycol ether.
43. The solubilized composition of Claim 39 wherein the solvent is a glycol ester.
44. The solubilized composition of Claim 39 wherein the solvent is a aprotic dipolar liquid.
45. The solubilized composition of Claim 39 wherein the solvent is an aromatic liquid.
46. The solubilized composition of Claim 39 wherein lhe surfactant is a betaine derivative. ,
47. The solubilized compositions of Claim 39 wherein the surfactant is cocamidopropyl betaine.
48. The solubilized compositions of Claim 39 wherein the surfactant is a non - ionic surfactant.
49. The solubilized compositions of Claim 39 wherein the surfactant is polyoxyethylene (20) monolaurate.
50. Biocidal compositions prepared by an acid -base reaction between a bioactive amine molecule having at lest one nitrogen with a free pair of electrons capable of being protonated by a bioactive acid.
51. Biocidal compositions as defined in Claim 50 wherein the base is. an azole antifungal compound being capable of forming an amine acid functionality with a bioactive acid .
52. Biocidal compositions as defined in Claim 51 wherein the azoies are cloconazole,clotrimazole, cyproconazole, fenbuconazoIe, myclobutanil. propiconazole , tebuconazole, tridimefon , and m icronazole.
53. Biocidal compositions as defined in Claim 50wherein the base is an antibiotic compound being capable of forming an amine salt functionality with a bioactive acid.
54 Biocidal compositions as defined in Claim 53 wherein the antibiotic consist of tetracycline, clindamycin, tazardiene, erythromyein , clinafloxaci n doxycycliπe, minocycline or lincomyein.
PCT/US2005/003671 2005-01-31 2005-01-31 Biocidal compositions WO2006085859A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020689A1 (en) * 2007-08-08 2009-02-12 General Electric Company Method for controlling protozoa that harbor bacteria

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3825560A (en) * 1969-12-30 1974-07-23 Y Sasaki N-monoacyl derivatives of arginine
US4980067A (en) * 1985-07-23 1990-12-25 Cuno, Inc. Polyionene-transformed microporous membrane
US5019096A (en) * 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
WO1992001380A1 (en) * 1990-07-18 1992-02-06 Imperial Chemical Industries Plc Biocide composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3825560A (en) * 1969-12-30 1974-07-23 Y Sasaki N-monoacyl derivatives of arginine
US4980067A (en) * 1985-07-23 1990-12-25 Cuno, Inc. Polyionene-transformed microporous membrane
US5019096A (en) * 1988-02-11 1991-05-28 Trustees Of Columbia University In The City Of New York Infection-resistant compositions, medical devices and surfaces and methods for preparing and using same
WO1992001380A1 (en) * 1990-07-18 1992-02-06 Imperial Chemical Industries Plc Biocide composition

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009020689A1 (en) * 2007-08-08 2009-02-12 General Electric Company Method for controlling protozoa that harbor bacteria

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