MXPA98010244A - Antimicrobial compositions - Google Patents

Abstract

Antimicrobial compositions comprising at least two antimicrobial agents exhibit reduced MIC values relative to the MIC for the agents making up the combination when measured alone. The compositions are useful as therapeutic agents such as in oral hygiene products.

Description

COMPOSITIONS ANTIMICRQBIRH & S FIELD OF THE INVENTION The present invention relates to antimicrobial compositions, products that incorporate these antimicrobial compositions and applications for antimicrobial compositions.

BACKGROUND OF THE INVENTION Periodontal disease and dental caries are of great economic and public health interest, worldwide. Now, it is highly recognized that these two oral diseases are caused by bacteria that grow in masses in the teeth and in the gingival area. A descriptive term commonly used for these bacterial masses is "dental plaque". In the case of periodontal disease, Schluger et al. (Scliluger, Youdelis, Page &Johnson, Periodontal Diseases, second edition, pages 153-262, Lea &Febiger, 1990) report that bacteria from dental plaque, which grow in the area where the teeth and gingival tissues are located, they cause an inflammation of the gingiva called gingivitis. "This is characterized by the gingiva (inflamed gum) that swells and bleeds easily. is inadequate, gingivitis can progress in "periodontitis" or periodontal disease in many individuals. Periodontitis in general is characterized by an inflammation of the tissues around the teeth, which leads to a resorption of the supporting bone. Periodontal disease is the leading cause of tooth loss among adults. Dental caries (cavities) ~ are also caused by bacteria, Streptococcus mutans is the main etiological agent (McGh.ee, Michalek &Cassell, Dental Microbiology, page 279, Harper &Row, 1982). The prevention of dental plaque or the removal of it has long been the focus of development, with the ultimate goal of inhibiting both caries and periodental diseases. While the formation of dental plaque can be inhibited to a certain degree by brushing the teeth at frequent intervals, gentle brushing is not sufficient to efficiently prevent the formation of dental plaque or to remove substantially all of the dental plaque that It has formed on the tooth. Since frequent gentle brushing is not sufficient to prevent the formation of dental caries or periodontal disease due to pathogenic plaque bacteria, chemical methods using antibacterial agents such as chlorhexidine, benzalkonium chloride, and cetylpyridinium chloride have been proposed. The use of natural products for the treatment The teeth and gums are ancient in the art, having been practiced and recommended since the mid-1880s. Since then, many patents have described compositions of oral products containing extracts of natural products. It is known that the compounds: hinokitiol, citral, geraniol, cocamidopropyl-betaine, berberine and enebrine essence, individually exhibit antimicrobial properties against certain bacteria. US Patent No. 3,940,476 discloses a method for inhibiting the formation of dental plaque, comprising topically applying to the teeth, as an active ingredient, an amount of either or a combination of: (a) allyl isothiocyanate, (b) uranium, (c) obtusaestirene, (d) citral, (e) citronellol, (f) nerol or J / g) geraniol. U.S. Patent No. 4,913,895 describes an oral composition that includes a linear polyphosphate or a cyclic polyphosphate and menthol, anethole or mixtures thereof in an aqueous medium. It is reported that the composition has antibacterial effects and prevents the development of stones and periodontal diseases. U.S. Patent No. 4,955,754 discloses that certain essential oils and combinations thereof possess antimicrobial properties against Aspergillus niger, Candida albicans, Staphylococcus aureus and Pseudomonas aeruginosa and, therefore, are useful as preservatives in cosmetic compositions. A mixture of 14 essential oils is described which provides desirable antimicrobial compositions against the indicated microorganisms. The combination described is described as suitable as a preservative for cosmetic compositions. The North American Patent No. 4, 999,184 describes oily compositions containing certain salts of pyrophosphate and reportedly provide an anticalculus benefit. U.S. Patent No. 5,316,760 describes a mouth care product that contains a combination of Drtica dioica extract and an extract of Juniperus communis. It is described that the combination of these extracts leads to a synergistic reduction of both dental plaque and bleeding and inflammation of the gingiva. The extract of Achillaea millefolium is also described as an additive suitable for the combination of Di-tica dioica and Juniperus communis extracts. U.S. Patent No. 5,472,684 discloses a composition that includes thymol and eugen, and optionally a sesquiterpene alcohol, such as fernesol, which allegedly has antiplaque and antigingivitis effects. The essence of the Australian tea tree, the sagebrush essence and the Eucalyptol is described as improving the antiplaque and anti-gingivitis activity of mouth rinses formulated from the compositions described. A property that characterizes the efficiency of an antimicrobial agent as antiplaque agent and anticalculus agent is the minimum inhibitory concentration or MIC of the agent. The MIC is the minimum concentration in micrograms per milliliter of an antimicrobial agent to which no bacterial growth is observed. At concentrations below the MIC, an antimicrobial agent is ineffective in eliminating or inhibiting the growth and reproduction of bacteria. The concentrations above the MIC, the antimicrobial agent is effective in the elimination or inhibition of the reproduction growth of the bacteria. Typically, antimicrobial agents are introduced into the oral cavity at an initial concentration. Almost immediately, the initial concentration begins to decrease due to the dynamics of the oral cavity. Eventually, the concentration of the antimicrobial agent within the oral cavity will fall below the MIC. In this way, it has been an object of those who work in developing antiplaque and anticalculus formulations to use antimicrobial agents that have low MICs. Chlorhexidine has a MIC of approximately one μg / ml and is the standard against which other antimicrobial agents. While chlorhexidine has a desirable MIC, it also exhibits an undesirable taste and has the undesirable side effect of staining the teeth.

SUMMARY OF THE INVENTION The present invention relates to the present discovery consisting in the addition of the antimicrobial agent described below to another antimicrobial agent described below, resulting in an unexpected and surprising reduction in the minimum inhibitory concentration (MIC) of at least one of the agents, when determined in the combination, that is, in the presence of another agent. In other words, the MIC for agent A, when the presence of agent B is measured, is lower than the MIC of agent A when measured alone, that is, in the absence of agent B. This way, when combined with agent B, the antimicrobial agent A is capable of effectively inhibiting or preventing bacterial growth at concentrations lower than the MIC for agent A measured alone. When the combination of agent A and agent B results in the CIM of agent B being reduced to a value below the CIM of agent B alone, the antimicrobial agent B is capable of effectively inhibiting or preventing bacterial growth, concentrations lower than the MIC for agent B alone. Put another way, when the agents A and B are in combination, at least one of the agents is capable of inhibiting or preventing the growth of the bacteria at a concentration below the concentration necessary to inhibit or prevent the growth of the bacteria when only one of the agents of the combination is present. Compositions for inhibiting the growth of bacteria formed in accordance with the present invention "include antimicrobial agent A and antimicrobial agent B, in effective amounts to prevent the growth of bacteria, wherein agent A and agent B are selected from the group consisting of: berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, hinokitiol, juicy fruit basil essence, juniper essence, basil essence of lemon, lemon essence, and Rosmarinus offícinalis essence An additional composition for inhibiting the growth of bacteria formed in accordance with the present invention includes geraniol and an antimicrobial agent - selected from the group consisting of: berberine, wood essence of cedar, chloramphenicol, citronella essence, cocamidopropyl-dimethylglycine, extract of Glycyrrhiza glabra, hinok itiol, essence of juicy fruit basil, essence of juniper, essence of lemon basil, essence of lemon and essence of Rosmarinus officinalis. In accordance with the present invention, the minimum inhibitory concentration of agent A in the presence of agent B is less than the minimum inhibitory concentration of agent A alone. In addition, preferably, the minimum inhibitory concentration of agent B in the presence of agent A is less than the minimum inhibitory concentration of agent B alone. The compositions of the present invention are effective in inhibiting or preventing the growth of bacteria such as: Actinomyces viscosus, Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis. In addition, the compositions formed according to the present invention may include a third antimicrobial agent C different from the antimicrobial agent A and the antimicrobial agent B, and selected from: berbexine, cedarwood essence, chloramphenicol, citral, citronella essence , cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, hinokitiol, juicy fruit basil essence, juniper essence, lemon basil essence, lemon essence, and Rosmarinus officinalis essence.

The compositions formed according to the present invention are useful in numerous products such as: cleansers, rinses, pharmaceuticals and oral hygiene products. The examples of oral hygiene products They include toothpastes and mouth rinses. Compositions for inhibiting the growth of the bacteria formed in accordance with the present invention can be used or contacted with the composition.

BRIEF DESCRIPTION OF THE DRAWINGS The Figure is a schematic illustration of the dilution scheme in a 96-well plate for a combination of three antimicrobial agents A, B, and C.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT As used herein, the following terms have the following meanings: "Berberine" refers to 5,6-dihydro-9,10-dimethoxybenzo [g] -1,3-benzodioxolo [5, 6-a] quinolizinium and salts thereof. Berberine is an alkaloid isolated from Hydrastis canadensis L. and several different plants in the Berberidaceae family. Example salts of berberine include berberine hydrochloride, berberine sulfate, and berberine sulfate. The Chemical number Abstract Service Registry (CAS) for berberine is 84603-60-1.

"Cedar wood oil" refers to extracts of complete, volatile oil, derived mainly from the heart of the ZTuniperus tree virginiana or Juniperus ashei. The constituents of the complete oil extract include tujopsen, cedrol, alpha-copaene, alpha-cedrene, beta-cedrene, and widdrol. The CAS number for the essence of cedar wood is 8000-27-9. "Chloramphenicol" refers to 2,2-dichloro-N- [2-hydroxyl-1- (hydroxymethyl) -2- (4-nitrophenyl) -ethyl] acetamide. Chloramphenicol is derived from Streptomyces venezuelae or by organic synthesis. The CAS number for chloramphenicol is 56-75-7. "Citral" refers to 3, 7-dimethyl-2,6-octadienal.

It is the volatile oil of Cymbopogon ci tratus and Cymbopogon flexuousus of the Gramineae family. Citral is available as a pure compound from commercial sources. The CAS number for citral is 5392-40-5. "Citronella oil" refers to a commercially available oil produced by steam distillation of either Cymbopogon nardus or Cymbopogon winterianus. The CAS number for citronella essence is 8000-29-1. "Geraniol" refers to trans-3,7-dimethyl-2,6-octadien-1-ol. The CAS number for geraniol is 106-24-1. Geraniol is found as a constituent in other essential oils such as citronella, lemon plant, rose essence, and palmarosa. "N-cosamidopropyl-dimethylglycine" has a CAS number 61789-40-0, 83138-0-3, and 86438-79-1.

"Glycyrrhiza glabra extract", also known as sweet stick extract, "refers to the crude powder extract of Glycyrrhiza glabra, Several varieties including G. tipica and G. glandulifera exist.The extract of Glycyrrhiza includes glycyrrhizic acid and glycyrrhetinic acid as constituents.The complete extract is available from commercial or commercial sources. it can be collected by solvent extraction, such as extraction with ethanol described below. "Hinocytol" refers to beta-tujuplicin, which is an extract of Thuja plicata. "Juicy fruit basil oil" refers to the complete extract of a variety sectioned basil with a juicy fruit component Juicy fruit basil is a cultivation of Ocl um baailicum L. "Juniper oil" refers to a complete, volatile oil extract from the ripe, dry fruit of Juniperus communis , Cupressaceae family - The essence of juniper is also known as juniper extract, Juniperus communis extract, juniper extract. CAS for the enebrine essence is 84603-69-0. "Lemon basil oil refers to the complete, volatile oil extract, from a selected variety of basil with a citral component.Lemon basil is an Ocimum crop jbasilicum L with a high citral content. "Lemon oil" refers to the complete, volatile oil extract, from a variety of fresh lemontrim shell. The essence of lemon is also known as lemon essence or citrus trus lemon essence. The CAS number for the lemon essence is 8008-56-8. "Rosmarinus officinalis oil" refers to the extract of complete oil, from one the flowering tips of Roamarinus officinalis. The essence of Rosmarinus officinalis is also known as the rosemary extract, or the essence extract of Rosmarinus officinalis. The CAS number for the essence of Rosmarinus officinalis is 84604-14-8. Additional information with respect to the essential oils described above can be found in Kirk-Othmer Encyclopedia of Chemical Technology, Fourth edition, volume 7, pages 603-674, John Wiley & Sons, Inc. All of the above is available from commercial sources. "Minimum inhibitory concentration or MIC" refers to the minimum concentration in micrograms per milliliter of an antimicrobial agent to which no growth of the bacteria is observed. The concentrations below the MIC, the antimicrobial agent is ineffective for annihilate or inhibit the growth and reproduction of bacteria. Concentrations above the MIC, the antimicrobial agent is effective in eliminating or inhibiting the growth and reproduction of bacteria. It has been observed that combinations of antimicrobial agents formed in accordance with the present invention exhibit a surprising and unexpectedly significant decrease in the MIC of at least one and, preferably, all the antimicrobial agents in the combination prepared at the MIC of a specific agent. the combination alone, that is, in the absence of the other agents. This surprising reduction in MIC has been observed in relation to gram-positive and gram-negative oral pathogenic bacteria, representative, such as: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, Streptococcus sanguis and Campylobacter rectus. For example, if the MIC for agent A is only 10 and the MIC for agent B is only 20, according to the present invention, when agent A and when agent B are combined, the MIC of agent A in the presence of agent B decreases in relation to the CIM of agent A only by an unexpected and surprising amount. In addition, preferably, the MIC of agent A in the presence of agent B decreases relative to the MIC of agent A only by an amount that is surprising and unexpected. This reduction in the CIM of agent A and agent B in the combination result in the ability of agent A, and preferably agent B to inhibit and / or prevent the growth and reproduction of bacteria at lower concentrations of antimicrobial agents A and B, in comparison if only the antimicrobial agent A or only the antimicrobial agent B is present as described in the background of the invention, typically, the concentration of the antimicrobial agents decreases from the time the agents are initially applied. In this way, by effectively decreasing the MIC of an antimicrobial agent, the period of time during which this antimicrobial agent can be expected to inhibit or prevent the growth of the bacteria is prolonged. The surprising and unexpected results associated with the present invention will be described in greater detail below and will be illustrated in the examples that follow. Combinations of antimicrobial agents formed in accordance with the present invention include: (1) Antimicrobial agent A selected from: berberine, cedar wood essence, chloramphenicol, citral, citronella essence, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, hinokitiol , essence of juicy fruit basil, enebrine essence, lemon basil essence, lemon essence, and essence of Rosmarinus officinalis; and (2) an antimicrobial agent B different from the antimicrobial agent A selected from the same list. In addition, combinations formed in accordance with the present invention include geraniol and an antimicrobial agent selected from berberine, cedar wood essence, chloramphenicol, citronella essence, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, hinokitiol, basil essence of juicy fruits, essence of juniper, essence of lemon basil, essence of lemon and essence of Rosmarinus officinalis. Of the many combinations of antimicrobial agents discussed above, preferred combinations include cedar wood essence and an antimicrobial agent selected from berberine, cedar wood essence, chloramphenicol, citral, citronella, cocamidopropyl-dimethylglycine, geraniol, ~ extract of Glycyrrhiza glabra, hinokitiol, juicy fruit basil essence, juniper essence, lemon basil essence, lemon essence, and essence of Rosmarinus officinalis. More preferred are combinations of cedar wood essence with berberine, cedarwood essence, chloramphenicol, citral, cocamidopropyl-dimethylglycine, geraniol, and Glycyrrhiza glabra extract, hinokitiol. Another preferred set of combinations include berberine and an antimicrobial agent selected from chloramphenicol, citral, geraniol, extract of Glycyrrhiza glabra, hinokitiol, essence of juicy fruit basil, essence of juniper, and essence of lemon basil. In the most preferred combinations with berberine are chloramphenicol, geraniol, extract of Glycyrrhiza glabra and essence of lemon basil. Other preferred combinations include hinokitiol in combination with chloramphenicol, citral, cocamidopropyl-dimethylglycine, geraniol, Glycyrrhiza glabra extract, enebrine essence, and lemon basil essence. Most preferred for the combination with hinokitiol are the antimicrobial agents "selected from chloramphenicol, cocamidopropyl-dimethylglycine, geraniol, and Glycyrrhiza glabra extract.Preferred results are obtained when the extract of Glycyrrhiza glabra is combined with antimicrobial agents selected from essence of cedar wood, chloramphenicol, geraniol, juicy fruit basil essence, juniper essence, lemon basil essence, lemon essence, and Rosmarinus officinalis essence.The most preferred for combination with Glycyrrhiza glabra extract are the Antimicrobial agents selected from essence of cedar wood, geraniol, enebrine essence, essence of Rosmarinus officinalis.

The above combinations of the indicated antimicrobial agents are preferred and are more preferred because: (1) the degree to which the MIC of the individual antimicrobial agents in the combination is reduced compared to the MIC of those agents when evaluated alone; and (2) the MIC for the agents-individual antimicrobials that are achieved due to the combination of the agents. In addition to compositions that include two antimicrobial agents as described above, the present invention also relates to compositions that include more than two antimicrobial agents, for example three to four, wherein the MIC of at least one of them and, preferably, , of all the constituent agents in the combination, are reduced in comparison to the MIC of those constituents determined alone. Accordingly, an antimicrobial agent C selected from the group set forth above, wherein the antimicrobial agent C is different from agent A and agent B and can be added to agent A and agent B to provide a three-component composition according to with the present invention. The compositions of the antimicrobial agents A, B and C formed according to the present invention provide compositions wherein the MIC of at least one of them and, preferably, of all the constituent agents, is reduce in comparison to the MIC of those constituents determined alone. In addition, in some cases, the MIC of constituents in the combination of the three antimicrobial agents is reduced in relation to the MIC of several pairs of the three constituent agents. The ratio of the antimicrobial agents in compositions formed in accordance with the present invention is not limited to any particular value with the proviso that the reduction of the MIC of the components of the combination is achieved as described above. The ratios for the two component compositions ranging from about 500: 1 to about 1: 500 have been found to provide surprising and unexpected reductions in the MIC. In the three component system, any agent can be related to the other two agents in a range of about 500: 1 to about 1: 500 to provide reductions in the MIC in accordance with the present invention. The particular amount of the antimicrobial agent present in compositions formed in accordance with the present invention is not limited to any particular value, provided that the amount present is effective to retard the growth of the bacteria and / or prevent the growth of the bacteria, it is say, in an amount that is greater than the MIC of the antimicrobial agent with respect to particular bacteria. When the compositions formed according to the present invention are incorporated with several vehicles, the amount of the antimicrobial agent present is preferably selected so that once the composition is applied or administered, the concentration of antimicrobial agents is greater than the concentration of the antimicrobial agent. MIC of the antimicrobial agent with respect to a particular bacterium. Suitable amounts vary from about 0.001 wt% to about 5.0 wt%, preferably about 0.01 wt% to about 2.5 wt% for each agent based on the total weight of the composition containing the agents. Compositions formed in accordance with the present invention are applied to surfaces where inhibition of bacterial growth is desirable. Examples of the products used to control the growth of bacteria on surfaces include cleansers, rinses, pharmaceuticals and, preferably, therapeutic products such as oral hygiene products, which include dentifrices, mouthwashes and mouthwashes. The components of these products that are combined with the compositions of the present invention are preferably selected such that they do not have an antagonistic effect on the MIC, decreasing the appearance of the compositions formed according to the present invention.

Dentifrices or toothpastes are, in general, a thick suspension of a polishing, abrasive material in an aqueous wetting system. Typically, the dentifrices include: an abrasive to remove the thin film, a humectant (s) to provide a vehicle for the flavor, an abrasive thickener (s) to structure and stabilize the toothpaste, a surfactant mainly to supply foam during use, a fluoride to prevent the formation of cavities and a flavoring to make the taste of the product pleasant. Many abrasives are available for dentifrices, examples include: silica xerogel, silica precipitate, dicalcium phosphate, dicalcium phosphate dihydrate, alumina trihydrate, calcium pyrophosphate, calcium carbonate and insoluble sodium metaphosphate. Examples of suitable humectants include sorbitols, glycerin, and polyethylene glycols. Silica aerogels, pyrogenic silica, silica precipitates, carboxymethylcellulose, carboxyvinyl polymers, xanthan gum and carrageenan, are examples of materials that are suitable as thickeners. Exemplary surfactants include sodium lauryl sulfate and dodecylbenzene sulfonate. Numerous flavoring agents are commercially available with those that provide peppermint flavors or other refreshing, such as cinnamon that is commonly used. Oral rinses or mouthwashes are in general, pourable, flavored aqueous emulsions, which in most cases have an antimicrobial incorporated. Typical components of an oral rinse include flavoring agents to make the product pleasant to use and to emphasize the therapeutic or cooling qualities, surfactant agent (s) to maintain stable dispersion flavor, humectant (s) to improve the mouthfeel, thickening agent and an active agent Frequently, a surfactant is used to impart light-foaming properties to oral rinsing.-Toothpastes and oral rinses that incorporate the compositions to inhibit the growth of bacteria formed in accordance with the present invention are formulated in a conventional manner with the antimicrobial agents that are present in an amount above their MICs as determined by the combination thereof The following examples illustrate the surprising and unexpected reduction in the MIC of the components when these components are combined in compositions to inhibit the growth of bacteria formed in accordance with the present invention.

EXAMPLE 1 Determination of the Minimum Inhibitory Concentration of Individual and Two Combined Antimicrobial Aqens The following example illustrates how the MIC of the individual antimicrobial agents that combine to form a composition according to the present invention and also illustrates how the MIC of the antimicrobial agents was determined in combination. A microtiter plate was used to dilute the antimicrobial agents at varying concentrations, in order to determine the MIC of these antimicrobial agents alone and the MIC of the agents when they were combined to form a composition according to the present invention. A bacterial culture was incubated at 37 ° C. Before dilution of the antimicrobial agents, as described below, the bacterial culture was stirred at 2,000 rpm in a pellet and redispersed in a buffered phosphate solution. The inoculum was normalized with a spectrophotometer at an optical density of 550 nanometer from 0.180-0.220 (equivalent to 5.0 -X 107 colony forming units, CFU per milliliter). The inoculum was separated, until the completion of the dilution of the antimicrobial agent. A 96-well polystyrene plate was used. sterile, to dilute the combinations of the surfactant A and the antimicrobial agent B. Using the aseptic technique, 100 microliters of distilled water were placed in each test cavity. The dilution scheme of the antimicrobial agents was separated into two parts, the first part is the dilution of agent A and the second part is the dilution of agent B. About one hundred microliters of the concentrated solution for agent A was placed in the first cavity of each column. This was a half dilution based on the concentration of the concentrated solution. About one hundred microliters were then transferred to the next step and so on in each of the test cavities. Each transfer represented a dilution at half the concentration of the preceding cavity. About one hundred microliters of the concentrated solution of agent B was then placed in the first cavity of each row and diluted through the plate in the same manner that agent B was diluted to the plate. After the dilution of agent B was completed, 80 microliters of growth medium specific for the bacteria under study was added to each cavity. In one column of the plate, 100 microliters of the concentrated solution for agent A was placed in the first well. Then 100 microliters was transferred to the next cavity and so on to each of the test cavities in the column. Each transfer was a 1/2 dilution of the preceding cavity concentration of agent A. The previous was repeated in another column using agent A. These two columns were used to determine the MIC for agent A alone and agent B alone . After the dilution of agent A alone and agent B alone was finished, 80 microliters of the specific growth medium for the bacteria under study were added to each cavity in these two columns. Twenty microliters of inoculum were then added to each cavity. This resulted in the first cavity having a final dilution of a quarter of the concentration of the concentrated dilutions. The remaining cavities were a half dilution and the preceding cavity for each transfer. The 96-well plate was incubated under conditions that varied based on the particular microorganisms. Aerobic bacteria: Actinomyces viscosus, Streptococcus mutans and Streptococcus sanguis were incubated under environmental conditions. Anaerobic bacteria. Fusobacterium nucleatum and Porphyromonas gingivalis were incubated under an atmosphere of 10% hydrogen, 5% carbon dioxide and the rest of nitrogen gas. After 48 hours of incubation, the incubated plate was read for microbial growth with a spectrophotometer, by optical density (OD). The well containing the lowest possible dilution for each agent via a spectrophotometer reading below 0.05 OD (ie, no detectable microbial growth) was considered representative for the combination. The MIC for each agent in the combination was determined by counting the concentration concentration of the concentrated solution and the resulting dilutions in the well plate 96. The specific bacteria inoculated in the 96-well plate are set forth in Table 1 below along with the growth medium and the incubation conditions for that microorganism.

Table Microorganism conditions / Growth medium / Incubation 1. Soy broth triptych 3.0% by weight by volume, yeast extract 0.1%, and 999 milliliters of distilled water. 2. Tryptic soy broth 3.0% by weight by volume, yeast extract 0.5%, L-cysteine 0.05%, Hemin 0.0005%, Menadione 0.0005%, and 990 milliliters of distilled water. 3. Tryptic soy broth 3.0% by weight to volume, yeast extract 0.5%, peptone 1.0%, extract of L-cysteine, Hemin 0.0005%, Menadione 0.00002%, and 990 milliliters of distilled water. The antimicrobial agents from which agent A and agent B were selected are set forth in Table 2 below Table 2 Berberine Chloride (BX1) Cedar Wood Essence (RCl) Chlorafenicol (CRl) Citral (CIT1) Citronella (CTR1) Cocamidopropyl dimethylglycine (TB1) Geraniol (GRA1) Glycyrrhiza glabra extract (GLY) Hinocytol (HK1) Essence of juicy fruit basil (JFB1) Essence of juniper (JPE1) Essence of lemon basil (LMB1) Essence of lemon (LM01) Essence of Rosmarinus officinalis (ROF1) In the following tables, the respective antimicrobial agents A and B, are identified with respect to the abbreviations set forth in Table 2. In addition, the five microorganisms set forth in Table 1 are referred to by the abbreviations set forth in Table 1. Various combinations of the antimicrobial agents set forth in Table 2 were evaluated according to the protocol set forth above in order to identify combinations of agents that will inhibit the visible in vitro growth of microorganisms and to evaluate the MIC of the agents in the combination. In addition, the lowest concentration, for example, (MIC), of each of the antimicrobial agents used in the two-component combinations that inhibited the in vitro growth of a particular microorganism was determined according to the protocol set forth above. The resulting data are summarized in Tables 3-16. In each of these tables, an average CIM value is given for agent A alone. Because multiple cavity plates were inoculated and "incubated according to the above procedure, in order to determine the information regarding their multiple combinations, in each run, a CIM for agent A was only determined. The CIM for agent A only given in Tables 3-16 represents the average of these values Table 3 IM of the cedar wood essence only v in combination with the antimicrobial agent B Table 4 CIM of Berberine Chloride only v in combination with the antimicrobial agent B Table 5 CIM of Hinokitiol alone and in combination with the antimicrobial agent B Table 6 IM of Glvcyrrhiza glabra extract alone and in combination with the antimicrobial agent B Table 7 CIM of Geraniol alone and in combination with the antimicrobial agent B Table 8 MIC of Chloramphenicol alone v in combination with the antimicrobial agent B Table 9 CIM of Citral alone and in combination with the antimicrobial agent B Table 10 CIM of Citronella Essence only v in combination with the antimicrobial agent B Table 11 CIM of juicy fruit basil essence only v in combination with the antimicrobial agent B Table 12 MIC of enebrine essence alone and in combination with the antimicrobial agent B Table 13 M of Essence of lemon basil only v in combination with the antimicrobial aqente B Table 14 IM of lemon essence only v in combination with the antimicrobial agent B Table 15 CIM of Essence of Rosmarinus offisinalis only v in combination with the antimicrobial agent B Table 16 CIM of Cocamidopropyl-dimethylglycine oil only v in combination with the antimicrobial agent B This example illustrates the effect that the addition of an antimicrobial agent B to the antimicrobial agent A has on the MIC of the antimicrobial agent A. The resulting data are illustrated as the MIC of agent A when combined with agent B is reduced in relation to the CIM of Agent A alone.

EXAMPLE 2 Determination of the MIC of Single Agents and Three Combined Antimicrobial Agents This example illustrates how combinations of three antimicrobial agents formed in accordance with the present invention inhibit the visible in vitro growth of oral microorganisms. In addition, the example describes how the MIC of the antimicrobial agents in the combinations is reduced in comparison to the MIC of those antimicrobial agents alone and the MIC of those agents in several pairs. Numerous combinations of the antimicrobial agents described herein were combined to form combinations comprising three antimicrobial or triplet agents. Each of the triplets formed included either cedar wood essence, berberine hydrochloride, or hinokitiol. The protocol used was a growth variation described above in Example 1. The titration was carried out in the two-dimensional arrangement of a 96-well plate. cavities In order to assess three agents, then the agents were put in pairs against the third agent. For example, the variable concentrations of the antimicrobial agent A plus the antimicrobial agent B against varying concentrations of the antimicrobial agent C were evaluated in a 96-well plate. The procedure was repeated with the other two possible pairs, that is, A + C with B, and B + C with A. Therefore, each triplet required three trials in order to assess each of the three possible pairs. The bacterial inoculum was prepared as described in Example 1. A sterile 96-well polystyrene plate was used to dilute the antimicrobial agents A, B and C. Using the aseptic technique, 100 microliters of distilled water was placed in each well. test pit. The dilution scheme was separated into two parts: first, the dilution of the combined agents A and B, and then second, the dilution of agent C. A dilution of agents A and B was achieved by placing 50 microliters of concentrated solution For agent A with the first cavity of each column, then 50 microliters of the concentrated solution for agent B was added to each of the first cavities of each column, therefore, the first step of each column included 50 microliters of entry solution for agent A and 50 microliters of concentrated solution for agent B. 100 microliters of the first row in each column then transferred to the next cavity in the column and so on down the column. Each transfer was a dilution to half the preceding concentration. The dilution of the antimicrobial agent C was achieved by adding 100 microliters of the concentrated solution of agent C to the first cavity of each row. 100 microliters of the first cavity in each row, then transferred to the next cavity and so on through the test well rows. Each transfer was a dilution at half of the preceding concentration. The Figure is a schematic illustration of the concentrations of the antimicrobial agents A, B and C, derived from the scheme described above. The concentrated solution for each antimicrobial agent has an initial concentration of 2,500 micrograms per milliliter. As illustrated in the Figured. , the concentration of agents A and B decreases in a given column. The concentration of agent C decreases through a row from left to right. At the end of the dilution of agent C, at least one column remained, which included dilute concentrated solution of A and B, with agent C. This well column was used to assess the MIC for agent A and agent B in combination. In addition, the concentrated solution of agent C was diluted in a column which gave an indication of the CIM for Agent C alone. 80 microliters of the growth medium specific for the bacteria under study were added to each cavity. The specific growth media for the bacteria are shown in Table 1. Then, 20 microliters of the inoculum was added to each cavity. This resulted in the first cavity having a final dilution of one-eighth of the concentrated solutions for agent A and agent B, and a one-fourth dilution of the concentrated dilution for agent C. The remaining cavities were a dilution to the half of the preceding cavity for each transfer. The 96-well plate was then incubated under conditions that vary by microorganisms. Table 1 lists the microorganisms and the specific incubation conditions. In addition to the bacteria set forth in Table 1, the bacteria Ca pylobacter rectus (CR) were used. The growth medium for Campylobacter rectus was 0.74% by weight in volume of brain and heart infusion broth, 0.01% yeast extract, 0.2% sodium formate, 0.03% sodium fumarate, and 0.005% hemin , and 990 milliliters of distilled water. The incubation conditions for Campylobacter rectus were 48 hours at 37 ° C under anaerobic conditions. The plate was then read for microbial growth with a spectrophotometer, by optical density. The well that contains the lowest dilution possible and to give agent with a spectrophotometer reading below 0.05 OD was considered representative for the combination. The MIC for each agent was then determined by counting the starting concentration of the concentrated solution and the resulting dilutions in the 96-well plates.

Table 17 CIM of Essences of Cedar Wood, Citral and Geraniol, alone, in Pairs and in Combination 'Directly to the right shows the MIC values for each agent when used alone. 2 Directly to the right shows the MIC values for each agent in the presence of a second agent. 3 Directly to the right shows the MIC values for each agent in the presence of two additional agents.

Table 18 CIM of Essences of Cedar Wood, Berberine Chloride and Geraniol, alone, in pairs and in combination Table 19 CIM of Red Cedar Wood Oil, Berberine Chloride and Hinokitiol, alone, in pairs and in combination Table 20 CIM of red Cedar wood oil, berberine chloride v Essence of juicy fruit basil, alone, in pairs and in combination Table 21 CIM of Cedar Wood Oil. Hino "kitiol v Gera iol, alone, in pairs and in combination Table 22 CIM of Cedar Wood Oil. Hinokitiol v Citral, alone. in pairs and in combination Table 23 CIM of Cedar Wood Oil, Hinokitiol and juicy fruit basil essence, alone, in Paree v in Combination Table 24 CIM of Cedar Wood Oil, Berberine Chloride and Citral in pairs, alone and in combination Table 25 CIM of berberine chloride. Hinokitiol and Geraniol. alone, in pairs and in combination Table 26 CIM of berberine chloride. Hinokitiol and Essence of juicy fruit basil, alone, in pairs and in combination Table 27 CIM of berberine chloride. Hinokitiol v Citral, alone, in pairs and in combination Table 28 CIM of Hinokitiol, Geraniol v Citral, alone, in pairs and in combination Table 29 CIM of Cedar Wood Oil, Geraniol and Juicy Fruit Basil Essence, Alone, in Pairs and in Combination Table 30 CIM of only Cedar Wood Oil. Essence of juicy and Citral fruit basil, alone, in pairs and in combination Table 31 CIM of Berberine Chloride. Essence of juicy and citrus fruit basil. alone, in pairs and in combination Table 32 CIM of only Berber Chloride. Essence of basil of luscious fruit and Geraniol, alone, in pairs and in combination Table 33 CIM of only Berberine Chloride, Citral and Geraniol, alone. in Pairs v in Combination Table 34 CIM of only Hinokitiol, Essence of juicy fruit basil and Citral, alone, in pairs and in combination Table 35 CIM of Hinokitiol. Essence of basil of ugly fruit and Geraniol, alone, in pairs and in combination This example illustrates how the MIC of the antimicrobial agents A, B and C in combination is reduced in relation to the MIC of the individual antimicrobial agents in the absence of other antimicrobial agents, EXAMPLE 3 Formulations of Dentrifics The following example describes dentrifices comprising combinations of the antimicrobial agents A, B and C formed in accordance with the present invention.

Table 36 Formulation 18-12: 0.2% Cedarwood Oil, Essence of juicy fruit basil at 0.1%, Citral at 0.02% (P / P) Table 37 Formulation 18-36: Cedarwood oil at 0.4% berberine chloride 0.01% (P / P) Table 38 m n 1 -: Ac ite de Mader Table 39 Formulation 18-37: Cedarwood Oil at 0.4 Geraniol at 0.1% v Citral at 0.05 '"% (P / P) Carbomer refers to polymer composed of crosslinked acrylic acid with allyl sucrose available as CARBOPOL * 940. CARBOPOL "940 is commercially available from BF Goodrich SYLODENT" 750 is a silica (silicon dioxide) gene and SYLODENT * 15 is a silica gene (silicon dioxide). SYLODENT "is commercially available from W.R. Grace &Co, - Conn. Davison Chemical Division.

Table 40 Formulation 18-58: 0.4% Cedar Wood Oil, 0.1% Geraniol (P / P) Poloxamer 407 is available under the trademark PLURONIC * F127 from BASF Corporation. PLURONIC "F127 is a non-ionic, difunctional block polymer that ends in primary hydroxyl groups with molecular weights ranging from 1,000 to about 15,000.They include polyoxyalkyl propylene glycol derivatives.The formulations described above were formed in a vacuum mixer upon addition. the deionized water and remove the carbomer while pulling a vacuum When the carbomer was well dispersed, the sodium hydroxide was added In another vessel, the 70% sorbitol solution and the Polaxamer were heated and mixed. Polaxamer was then added to the vacuum mixture and mixed in the carbomer mixture.The xanthan gum was then added to the glycerin, and the resulting solution was added to the vacuum mixer and incorporated into the mixture. to the vacuum mixer, followed by the silicas that slowly mixed.

The active agents, flavor, sodium lauryl sulfate and coloring agents were then added and allowed to mix until they were well incorporated.

EXAMPLE 4 ACCEPTANCE OF THE CONSUMER This example illustrates consumer acceptance of dentifrice formulations incorporating combinations of antimicrobial agents A, B, and optionally C formed in accordance with the present invention. The formulations set forth above in Tables 36-40 were evaluated for consumer acceptance. Formulations 5-99 was a commercially available dentifrice such as ListerineE Cool Mint gel- - The preferred study was carried out with a group of approximately 20 people. A tube of toothpaste formulation was given to each person to use during the course of a week. At the end of the week, participants filled out a questionnaire, the results of which are summarized in Table 41 below. The score interval was 1-10 with one that is poor and with 10 that is good. The scores were counted and averaged.

Table 41 Consumer assessment This example illustrates that the complete consumer satisfaction for formulations with antimicrobial agents according to the present invention is greater than the complete satisfaction of the consumer for the commercially available product, ListerineE Col Mint gel.

EXAMPLE 5 EXTRACTION WITH ETHANOL FROM G YCYRSBIZÍ. GABRA 25 grams of powdered plant material of Glycyrrhiza glabra was combined with 250 grams of a 250 gram mixture of a 95: 5 ethanol / water mixture. The mixture was stirred overnight at room temperature. The solids were removed from the stirred mixture with a Whatman filter number 4 in a Buchner funnel. The additional removal of the solids was achieved with a Whatman filter number 5 in a Buchner funnel. Additional solids were removed with a Whatman 1 micrometer filter in a Buchner funnel. A vacuum filtration apparatus and a 0.2 micron filter was used to clean the solution in a final time. The clean solution was then concentrated to a solid using a rotoevaporizer. Approximately 2.5 grams of an oxide-colored solid was collected as the crude extract of Glycyrrhiza glabra. While the preferred embodiment of the invention has been illustrated and described, it will be appreciated that various changes may be made therein without departing from the spirit and scope of the invention.

Claims (43)

1. CLAIMS: 1.
2. A therapeutic composition for inhibiting the growth of bacteria, comprising: an antimicrobial agent A and an antimicrobial agent B in amounts effective to inhibit the growth of bacteria; Agents A and B are selected from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, cocamidopropyl-dimethylglycine, extract "of Glycyrrhiza glabra, hinokitiol, essence of juicy fruit basil, essence of juniper, essence of lemon basil, lemon essence, and essence of Rosmarinus officinalis 2.
3. The composition according to claim 1, wherein the minimum inhibitory concentration for agent A in the presence of agent B is less than the concentration minimal inhibitory agent A alone 3.
4. The composition according to claim 2, wherein the minimum inhibitory concentration for agent B in the presence of agent A is less than the minimum inhibitory concentration of agent B alone. claim 3, wherein the bacteria are oral pathogenic bacteria selected from the group consisting of Actinomyces viscosus, Fusobacterium nucleatum , Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis.
5. 5. The composition according to claim 1, wherein agent A is essence of cedar wood. The composition according to claim 5, wherein the agent B is selected from the group consisting of: berberine, chloramphenicol, citral, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, hinokithiol, juicy fruit basil essence, and essence of Rosmarinus officinalis. The composition according to claim 6, wherein agent B is selected from the group consisting of: berberine, chloramphenicol, citral, cocamidopropyl-dimethylglycine, and Glycyrrhiza glabra extract. 8. The composition according to claim 1, wherein agent A is berberine. The composition according to claim 8, wherein the agent B is selected from the group consisting of: chloramphenicol, citral, Glycyrrhiza glabra extract, hinokitiol, juicy fruit basil essence, enebrine essence, basil essence of lemon. The composition according to claim 9, wherein the agent B is selected from the group consisting of: chloramphenicol, Glycyrrhiza glabra extract and limon basil essence. 11. The composition according to claim 1, in where agent A is hinokitiol. The composition according to claim 11, wherein the agent B is selected from the group consisting of: chloramphenicol, citral, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, enebrine essence, lemon basil essence. 13. The composition according to claim 12, wherein agent B is selected from the group consisting of: chloramphenicol, cocamidopropyl-dimethylglycine, and Glycyrrhiza glabra extract. 14. The composition according to claim 1, wherein agent A is Glycyrrhiza glabra extract. 15. The composition according to claim 14, wherein the agent B is selected from the group consisting of: chloramphenicol, cocamidopropyl-dimethylglycine, basil essence of juicy fruits and lemon basil essence. 16. The composition according to claim 15, wherein the agent B is selected from the group consisting of: chloramphenicol and cocamidopropyl-dimethylglycine. The composition according to claim 1, further comprising an antimicrobial agent C different from the antimicrobial agent A and the antimicrobial agent B, the agent C which is present in an amount effective to inhibit the growth of the bacteria and is selected from from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, cosamidopropyl-dimethylglycine, extract of Glycyrrhiza glabra, hinokitiol, essence of juicy fruit basil, essence of juniper, essence of lemon basil , essence of lemon and essence of Rosmarinus officinalis. 18. An oral hygiene product, comprising: an antimicrobial agent A, comprising geraniol; and an antimicrobial agent B selected from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citronella essence, cocamidopropyl-dimethylglycine, Glycyrrhiza glabra extract, juicy fruit basil essence, enebrine essence, essence of lemon basil, lemon essence, and Rosmarinus officinalis essence, the antimicrobial agent A and the antimicrobial agent b are present in an amount effective to inhibit the growth of the oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Steptococcus sanguis. The product according to claim 18, further comprising an antimicrobial agent C different from the antimicrobial agent a and the antimicrobial agent b selected from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citronella essence, Glycyrrhiza glabra extract, juicy fruit basil essence, juniper essence, limon basil essence, lemon essence, and Rosmarinus officinalis essence. 20. An oral hygiene product, comprising the composition of claim 18. 21. A method for inhibiting the growth of oral pathogenic bacteria, selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans , and? treptococcus sanguis within an oral cavity, comprising the steps of contacting the oral cavity with the product of claim 18. 22. The oral hygiene product, comprising: the antimicrobial agent A and the antimicrobial agent B in an amount effective to inhibit the growth of oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis wherein agents A and B are selected from the group consists of: Berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, Glyc extract yrrhiza glabra, essence of juicy fruit basil, essence of encocamidopropyl-dimethylglycine, Glycyrrhiza extract, juicy fruit basil essence, juniper essence, essence of limon basil, and Rosmarinus officinalis essence. 23. The oral hygiene product according to claim 22, wherein the minimum inhibitory concentration for agent A relative to at least one of the bacteria, the presence of agent B, is synergistically lower than the minimum inhibitory concentration of agent A alone. 24. The oral hygiene product according to claim 23, wherein a minimum inhibitory concentration of agent B with respect to at least one of the bacteria, the presence of agent A, is synergistically lower than the minimum inhibitory concentration of agent B alone. 25. The oral hygiene product according to claim 24, wherein the bacteria are oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas ginglvalis, Streptococcus mutans, and Streptococcus sanguis. 26. The oral hygiene product according to claim 22, wherein the agent A is selected from the group consisting of: Decarbon wood essence, Berberine, and extract of Glycyrrhiza glabra. 27. The oral hygiene product according to claim 22, further comprising the antimicrobial agent C, different from agent A and agent B, agent C which is present in an amount effective to inhibit the growth of bacteria and is selected from from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, extract of Glycyrrhiza glabra, essence of juicy fruit basil, essence of juniper, essence of basil lemon, essence of lemon, and essence of Rosmarinus officinalis. 28. A method for inhibiting the growth of bacteria within an oral cavity, comprising the step of: contacting the oral cavity with a composition that includes the antimicrobial agent A and the antimicrobial agent B in an amount effective to inhibit growth of the oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis, agents A and B, selected from the group consisting of: Berberine, wood essence of cedar, chloramphenicol, citral, citronella essence, Glycyrrhiza glabra extract, essence of basil of juicy fruits, essence of juniper, essence of lemon basil, essence of lemon, and essence of Rosmarinus officinalis. The method according to claim 28, wherein the minimum inhibitory concentration of agent A relative to at least one of the bacteria in the presence of agent B, is synergistically lower than the minimum inhibitory concentration of Agent A alone. 30. The method according to claim 29, wherein the minimum inhibitory concentration of agent B with respect to at least one of the bacteria, the presence of agent A, is synergistically lower than the minimum inhibitory concentration of agent B alone. 31. The method according to claim 30, wherein the bacteria are oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis. 32. The method according to claim 28, wherein the antimicrobial agent A is selected from the group consisting of: cedar wood essence, berberine, and Glycyrrhiza glabra extract. 33. The method according to claim 28, wherein the composition including the antimicrobial agents A and B further comprises an antimicrobial agent C different from agent A and agent B, agent C selected from the group consisting of: Berberine, essence of cedar wood, chloramphenicol, citral, citronella essence, Glycyrrhiza glabra extract, juicy fruit basil essence, juniper essence, lemon basil essence, lemon essence, and essence of Rosmarinus officinalis. 34. A method for reducing the minimum inhibitory concentration relative to the oral pathogenic bacteria selected from the group consisting of: a. antimicrobial agent A selected from the group consisting of: Actmomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis, of an antimicrobial agent A selected from the group consisting of: Berberma, essence of cedar wood, chloramphenicol, citral, citronella essence, geraniol, Glycyrrhiza glabra extract, juicy fruit basil essence, juniper essence, lemon basil essence, lemon essence, and Rosmarinus officinalis essence, which comprises: combining agent A with an antimicrobial agent B different from agent A, agent B selected from the group consisting of: Berberma, essence of cedar wood, chloramphenicol, citral, citronella essence, geraniol, extract of Glycyrrhiza glabra, essence of juicy fruit basil , essence of juniper, essence of lemon basil, essence of lemon, and essence of Rosmarinus officinalis, the minimum inhibitory concentration of agent A in the presence of agent B which is less than the minimum inhibitory concentration of agent A alone. 35. The method according to claim 34, wherein the step of combining agent B with agent A results in a synergistic reduction in the minimum inhibitory concentration of agent A. 36. The oral hygiene product according to claim 18, in wherein the antimicrobial agent B is selected from the group consisting of: enebrine essence, lemon basil essence, lemon essence, Rosmarinus officinalis essence, and cedar wood essence. 37. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is cedar wood essence and the antimicrobial agent B is selected from the group consisting of: Berberine and Glycyrrhiza glabra extract. 38. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is Glycyrrhiza glabra extract, and the antimicrobial agent B is selected from the group consisting of: citronella essence, juicy fruit basil scent, essence of juniper, and essence of Rosmarinus officinalis. 39. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is chloramphenicol and the antimicrobial agent B is lemon essence. 40. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is citral and the antimicrobial agent B is selected from the group consisting of: citronella essence, juicy fruit basil essence, enebrine essence, essence of lemon basil, lemon essence, and Rosmarinus officinalis essence. 41. The oral hygiene product according to claim 22, wherein the antimicrobial agent a is citronella essence and the antimicrobial agent B selects from the group consisting of: essence of juicy fruit basil, essence of juniper, lemon essence, essence of Rosmarinus officinalis. 42. The oral hygiene product according to claim 22, wherein the antimicrobial agent a is a juicy fruit albahasa essence and the antimicrobial agent B is selected from the group consisting of: enebrine essence, essence of lemon basil, and essence of Rosmarinus officinalis. 43. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is enebrine essence, and the antimicrobial agent B is selected from the group consisting of: lemon basil essence, lemon essence, and essence of Rosmarinus officinalis. Four . The oral hygiene product according to the claim 22, wherein the antimicrobial agent A is essence of limon basil and the antimicrobial agent B is selected from the group consisting of: lemon essence, and Rosmarinus officinalis essence. 45. The oral hygiene product according to claim 22, wherein the antimicrobial agent A is lemon basil essence and the antimicrobial agent B is lemon basil essence and the antimicrobial agent ~ B is the essence of Rosmarinus officinalis. 46. An oral hygiene product, comprising: An antimicrobial agent A comprising cocamidopropyl-dimethylglycine; and An antimicrobial agent B selected from the group consisting of: Berberine, cedar wood essence, chloramphenicol, citral, citronella essence, Glycyrrhiza glabra extract, juicy fruit basil essence, juniper essence, albahasa essence lemon, lemon essence, and essence of Rosmarinus officinalis, the antimicrobial agent A and the antimicrobial agent B which are present in an amount effective to inhibit the growth of the oral pathogenic bacteria selected from the group consisting of: Actinomyces viscosus, Fusobacterium nucleatum, Porphyromonas gingivalis, Streptococcus mutans, and Streptococcus sanguis. 47. A method to reduce concentration minimal inhibitory of an antimicrobial agent A comprising cocamidopropyl-dimethylglycine, comprising: Combine agent A with antimicrobial agent B different from agent A, agent B is selected from the group consisting of: Berberine, cedar wood essence, chloramphenicol, citral, citronella essence, geraniol, Glycyrrhiza glabra extract, juicy fruit basil essence, juniper essence, limon basil essence, lemon essence, and Rosmarinus officinalis essence, the minimum inhibitory concentration of agent A in the presence of agent B which is less than the minimum inhibitory concentration of agent A alone.