KR20140055885A - The gargle composites for the increment of the oral care - Google Patents

Abstract

The present invention relates to a gargle composition not using alcohol causing a dry mouth, and also using a nontoxic natural material instead of using synthetic preservative and antimicrobial agent, to suppress and remove a malodorous substance and an organism causing malodor and, more specifically, to a composition for improving oral hygiene improving an antimicrobial activity increasing effect for an organism causing bad breath and an organism causing oral mucous membrane infection, a plaque build-up suppressing effect, and a gingivitis releasing effect by an appropriate mixing of phytoncide essential oil, a water-soluble chitosan, and eucalriptol having a periodontal disease preventing effect.

Description

[0001] The present invention relates to a composition for enhancing oral hygiene,

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The present invention uses not only an alcohol causing dry mouth syndrome but also a non-toxic natural product instead of a synthetic preservative and an antimicrobial agent suspected of side effects, thereby suppressing and eliminating odor causing substances and causative bacteria which cause bad breath More particularly, the present invention relates to a composition for inhibiting halitosis, and more particularly, to a composition for preventing oral malodor, A plaque formation inhibiting effect, and an effect of alleviating gingival inflammation.

Hereinafter, the present invention will be described in more detail.

In the mouth there are many microorganisms that decompose proteins and amino acids. It is caused by the decomposition of amino acids produced by microorganisms in the oral cavity, such as glycolipids and food waste in saliva, by a demineralization enzyme or an amino enzyme to generate a malodorous substance. Therefore, bad breath is primarily caused by bacterial spoilage caused by bacteria, or by sulfide contained in these substances when garlic or pepper is consumed. If you have bad breath, you should consider whether there is periodontal disease or lack of oral care. Volatile Sulfide Compounds (hereinafter abbreviated as "VSC") are the main ingredients that cause bad breath. These volatile sulfides include hydrogen sulfide (H2S), methyl mercaptan (CH3SH), dimethyl mercaptan , (CH3) 2S], and methyl mercaptan is known to be the main component of malodorous odor in halitosis. In the case of fish, trimethylamine ([CH3] 3N] or [delta] -aminovaleric acid, which is in the form of fish flesh, is formed as the freshness of the fish is decreased, and these volatile amine compounds, especially trimethylamine This is a major part of this odor component. Other bad breath inducing substances include aldehyde, fatty acid, ammonia or pyridine.

Korean Patent Publication No. 97-8154 and Japanese Patent Application Laid-Open No. 60-7548 also claim the right to suppress bad breath by removing such VSC.

However, in order to effectively inhibit bad breath, it is essential to remove the oral microorganisms and treat oral inflammation.

Also, it is necessary to remove odor causing substances generated in the oral cavity and intestines. However, the above-mentioned methods have not yet solved the problem and development of a composition for promoting oral hygiene is required.

The oral dentifrice composition may include a solubilizing agent, a wetting agent, a solvent, a flavoring agent, a sweetening agent, an antiseptic, a buffering agent, a pigment, and the like. However, as discussed below, it should be noted that many of the ingredients present in most current mouthwashes marketed in the country may cause side effects.

If mouthwash is applied after brushing, the mucous membrane is stimulated by alcohol and infection of fungi such as mouth candidiasis, which is caught in the mouth during long-term use, may occur. Oral cleansers can also discolor tooth or tongue.

In November 2008, Bahrain researchers conducted a study of 293 adults aged 18 years and over who had bad breath symptoms, suggesting that antibacterial mouthwashes such as chlorhexidine or cetylpyridinium chloride remove germs that cause posterior teeth in the tongue, Which can be discolored.

However, in the case of elderly people who have dry mouth or dry mouth, it is better not to use oral cleansers, which contain a lot of alcohol after brushing, because they can cause more severe symptoms.

About the side effects of 'chlorhexidine' ingredient, the Ministry of Health, Labor and Welfare of Japan announced in 2003 that chlorhexidine gluconate, which is commonly used in oral cleansers and toothpastes, is causing a shock.

In Korea, mouthwash is divided into pharmacies, supermarkets, quasi-drugs that can be freely purchased, and specialty medicines that can be bought by doctors' prescriptions in hospitals. Many products contain chlorhexidine components, but most of them do not know about the hazards.

"The chlorhexidine ingredient is mainly contained in oral cleansers classified as specialty medicines, but it is partly contained in quasi-drugs, but the concentration is lower than that contained in medicines," said a note on the back of the product. "He said.

Most of the mouthwashes used in hospitals for treatment are chlorhexidine, which is recommended for a short period of time.

Quasi-drugs, however, can be a problem because they can be purchased easily, even if they are not prescribed by the hospital.

In case of mouthwash containing chlorhexidine ingredient, it may cause various side effects if it is used for a long time.

The following ingredients are frequently used in conventional mouthwashes.

The solubilizer gives a cooling sensation when used in the product, and it can dissolve fragrance or preservative that does not dissolve in water. Alcohols, polyoxypropylene copolymerized polymers, polyoxyethylene hydrogenated castor oil, high alkyl acetates, and polyoxyethylene derivatives of sorbitan fatty acid esters, from which one or more selected ingredients can be added in an amount of from 20 to 60 wt. %, Preferably 5 to 20 wt%, based on the total weight of the composition.

The wetting agent serves to impart stability, sweet taste and slight viscosity of the product. Glycerin, sorbitol solution, polyethylene glycol, etc. are used alone or in admixture of two or more kinds in an amount of 20 to 60% by weight, preferably 20 to 50% by weight.

The preservative is used in an amount of 0.05 to 0.25% by weight, such as methylparaben, p-hydroxybenzoate and propylparabenoxybenzoate. Although Korea Food and Drug Administration (KFDA) has proposed the use amount, the following side effects have been reported when it is overexposed. It reacts with oxalic acid to stimulate central nerve paralysis, hemorrhagic gastritis, liver adverse effects, carcinogenic chromosomal abnormalities, eyes, and skin mucosa. Parabens (methylparaben, ethylparaben, propylparaben, etc.) are widely used as preservatives in cosmetics. They are classified as harmful substances because they are known to cause endocrine disruption, skin aging, and breast cancer if they are absorbed into the human body.

As the pH adjusting agent, it is preferable to use 0.02 to 1.5% by weight of phosphoric acid, sodium phosphate, citric acid, sodium citrate, succinic acid, sodium succinate, tartaric acid, sodium tartrate or the like.

Examples of the material constituting the fragrance include a fragrant oil, a clove oil, a lemon, a wight grease, a methyl salicylate, a cinnamon oil, a cinnamic Aldehyde and other perfume ingredients are used, and the ingredients constituting the perfume are used in an amount of 0.1 to 2.0% by weight, preferably 0.5 to 1.5% by weight, by mixing one or more of the above ingredients.

Disclosure of the Invention The present invention provides a composition for promoting oral hygiene that is excellent in antibacterial activity against oral microorganisms, oral antiinflammatory activity, and ability to remove badodurative substances, The purpose.

The present invention relates to an oral composition for suppressing and eliminating bad breath caused by bad breath caused by halitosis, and more particularly to an oral composition for inhibiting halitosis by containing pine essential oil and green tea extract as active ingredients.

Accordingly, the present inventors have studied a method for solving the problems of the above-mentioned antimicrobial substances while containing all the substances capable of removing bad breath inducing substances and bad breath causative bacteria in order to provide an oral composition excellent in the effect of inhibiting bad breath As a result, it was found that cetylpyridinium chloride, which has excellent antimicrobial effect, is mixed in a specific amount to complement the continuous effect, and also has good antibacterial and deodorizing effect, which is safe to human body, And the green tea extract may be mixed in a specific amount to achieve the above object, and the present invention has been completed. In addition, using stevioside, a natural sweetener, instead of saccharin, which is an artificial sweetener, aims to create a composition ratio that not only alleviates general concern about human safety but also increases the sensation of cooling in use.

As described above, the composition for suppressing bad breath according to the present invention can be used by appropriately mixing the eucalyptus essential oil and xylitol as the main active ingredient within the range of the present invention.

Disclosure of the Invention The present invention provides a composition for promoting oral hygiene that is excellent in antibacterial activity against oral microorganisms, oral antiinflammatory activity, and ability to remove badodurative substances, The purpose.

The present invention relates to an oral composition for suppressing and eliminating bad breath caused by halitosis, and more particularly to an oral composition for inhibiting halitosis by containing pine essential oil, an aqueous solution of chitosan and eucalyptol as an active ingredient.

Accordingly, in order to provide an oral composition excellent in the effect of suppressing bad breath, the inventors of the present invention have found that when all the substances capable of eliminating the bad breath inducing substances and the bad breath causative bacteria are contained, natural substances used in the conventional products are mixed in an appropriate amount And to develop a composition capable of maximizing the antimicrobial activity and exhilaration.

As described above, the oral composition according to the present invention can provide an excellent effect on the antibacterial activity and the bad breath removing ability through synergistic action of the pharmacological components. Also, by not using alcohol that causes side effects such as dry mouth, it can reduce the concern about health safety of the general public.

In order to attain the above object, the oral composition of the present invention contains 0.001 to 1.0 wt% of pine essential oil, 0.01 to 5.0 wt% of euclitol, 0.01 to 1.0 wt% of chitosan and 0.001 to 0.1 wt% of copper sulfate pentahydrate .

Hereinafter, the present invention will be described in more detail.

The composition for oral use of the present invention is a composition for oral care of non-alcoholic preservatives and non-alcoholic beverages which does not use alcohol that causes dry mouth in the oral cavity, instead of using synthetic antimicrobial agents for which side effects are reported, Respectively.

In addition, it was confirmed that it has a characteristic of preventing oral mucosal infections (oral candidiasis) and vaginal infections, which frequently occur in infants and women. Oral candidiasis is a type of infectious disease. It appears as a fine white deposit on the red spot on the oral mucosa, or as a soft, raised white spot, like condensed milk. When rubbed with cotton or gauze, the membrane is peeled off, followed by a red mucosal surface. Food comes into contact with this place, causing pain and biting. These oral mucosal infections caused by Candida albicans are separated from the mucous membranes of healthy individuals, which are caused by infiltration into the oral mucosa when the immune system weakens. Causes are those that are caused by diseases with malnutrition such as malnutrition, diabetes, rheumatoid arthritis, and are often caused by weakness of immunity such as long-term use of antibiotics, corticosteroids and immunosuppressants. In the case of oral candidiasis, the mother is often infected. In the elderly, it is often reported that the denture is not cleaned properly or under the dentures.

First, each component contained in the oral composition of the present invention will be described as follows.

(1) Pine tree essential oil

Essential oils are mainly produced in plants but they are usually found in oil glands or glandular hair or in the form of melted resin. Essential oils generally contain terpene compounds, aliphatic chain compounds and aromatic compounds. For example, alpha-pinene, beta-pinene, camphene, and sabinene. These mixtures or each of them have been widely used for herbs, fragrances and herbal medicines for a long time by expressing deodorant, deodorant, fragrance and pleasant feeling as well as antibacterial and insecticidal effect. Nowadays, phytoncide is better known as phytoncide, and is attracting attention as aroma therapy, cosmetic raw materials, and pharmaceutical raw materials. Among them, the essential oil extracted from Pinus koraiensis is known to be non-toxic to the human body, unlike the essential oils of other softwoods.

Steam distillation was used for the production of pine tree essential oil.

This essential oil of pine tree is contained in an amount of 0.001 to 1.0% by weight based on the total weight of the composition. In general, when the content of the green tea extract is increased, the effect of removing the bad breath of the composition is increased, but the stability of the composition with time is lowered. Therefore, when the concentration exceeds 1.0% by weight, the layer separation phenomenon occurs during storage at room temperature. There is a problem of deterioration of the bad breath, and when it is less than 0.001% by weight, the bad breath removing effect can not be obtained.

(2) C31G

Certain mixtures of amines are known to be effective antimicrobial agents against gram negative and gram positive bacteria. (A) alkyl-N-betaine, alkyl-N-sulfobetaine, acyl-N-betaine, alkyl N- substituted amino propionic acid or alkyl imidazolinium betaine and (b) It is known that certain mixtures of dimethylamine oxides, alkyl-N, N-dihydroxyethylamine oxides or acylamide t-amine oxides can be used for skin germ removal, purification and deodorization (see, for example, EB Michaels US Pat. No. 4,183,952; US Pat. No. 4,075,350 to EB Michaels; and US Pat. No. 4,107,328 to EB Michaels). These compositions are also useful for prolonged inhibition of body odor. Mixtures of the same active ingredients are also known to enhance oral hygiene by eliminating oral microorganisms and inhibiting the formation of jigs (US Pat. No. 4,839,158 to E. B. Michaels). This type of composition is also known to be an effective fungicide (Corner, AM, Antimicrobial Agents and Chemotherapy, 32 (3): 350-353 (1988, 3); Corner, AM, Journal of Clinical Dentistry, Vol. 2 (3): 35-38 (1990)). (See also U.S. Pat. Nos. 4,075,350, 4,107,328, 4,183,952 and 4,839,158, issued to E. B. Michaels). It is also known that non-ionic surfactants possessing ether or amide linkages between the hydrophilic and hydrophobic sites of the molecule rapidly inactivate the infectivity of herpes simplex viruses I and II (Asculai, SS et al., Microbiology Chemotherapy Vol. 13: P 686-690 (1978)). The composition used in the process of the invention consists of a mixture of betaines and amine oxides. The betaine used in the present invention may be selected from (a) alkyl-N-betaines, alkyl-N-sulfobetaines, acyl-N-betaines, alkyl N-substituted aminopropionic acids, alkylimidazolinium betaines, And mixtures thereof. Typically, they have two lower alkyl groups on the nitrogen atom. Most effectively they have two methyl substituents on the nitrogen atom. The amine oxides used in the present invention are selected from the group consisting of (b) alkyl-N, N-dimethylamine oxides, alkyl-N, N-dihydroxyethylamine oxides or acylamide t-amine oxides and mixtures of two or more thereof do. Typically, the betaine and amine oxide components are present in a molar ratio of 1: 5 to 5: 1, preferably 1: 1. Alkyl-N-sulphobetaine, acyl-N-betaine, alkyl-N-substituted amino propionic acid and alkyl imidazolinium betaine ( Each of which is also referred to as cocoamphoacetate) has the following structure:

In an amount of 0.001 to 1.0% by weight based on the total weight of the composition.

Wherein R is a higher alkyl group having 10 to 18 carbon atoms, preferably 12 to 16 carbon atoms.

The term lower alkyl as used herein means an alkyl group of one to three carbon atoms.

Examples of these mentioned substances include (1) oleoyl-N-beta- 12-3, coco-N-betaine, cetyl-N-betaine, stearyl- Yl-N-betaine; (2) coco-N-sulfobetaine, cetyl-N-sulfobetaine, stearyl-N-sulfobetaine, isostearyl-N-sulfobetaine, oleyl-N-sulfobetaine; (3) A pharmaceutical composition comprising a compound selected from the group consisting of cocoamido-N-betaine, cetylamido-N-betaine, stearylamido-N-betaine, isostearylamido- ; (4) N-coco-2-aminopropionic acid, N-stearyl-2-aminopropionic acid, N-stearyl- (2-aminopropionic acid), N-coco-bis (2-aminopropionic acid), N-cetyl-bis (2-aminopropionic acid) ); (5) N-lauryl-bis (2-aminopropionic acid) 1-hydroxyethyl-1-carboxymethyl-2-decylimidazolium betaine; 1-hydroxyethyl-1-carboxymethyl-2-dodecylimidazolium betaine; 1-hydroxyethyl-1-carboxymethyl-2-stearylimidazolium betaine; 1-hydroxyethyl-1-carboxymethyl-2-oleyldidazolium betaine; Or mixtures thereof.

As used herein, the term " coco " is used in the CTFA (name of Cosmetic and Toiletry and Fragrance Association, Wash., DC) and refers to a mixture of alkyl groups present in coconut oil, i.e. alkyl groups of 10 to 18 carbon atoms . The names of the compounds listed herein are those of CTFA. (1) alkyl-N, N-dimethylamine oxide, (2) alkyl-N, N-dihydroxylethylamine oxide, or (3) acylamide t-amine The oxides each have the structure:

Wherein R is a radical such as a higher alkyl group of 10 to 18 carbon atoms such as decyl, undecyl, lauryl, tridecyl, myristyl, cetyl, stearyl, isostearyl or oleyl. Examples of amine oxides include decyl-N, N-dimethylamine oxide, lauryl-N, N-dimethylamine oxide, stearyl-N, N-dimethylamine oxide, oleyl- N, N-dihydroxyethylamine oxide, N, N-dihydroxyethylamine oxide, cetyl-N, N-dihydroxyethylamine oxide, oleyl- N, N-dihydroxyethyl-amine oxides, and mixtures thereof.

(3) Chitosan

The chitosan used in the present invention is a natural polysaccharide derived from natural sources. The amount of chitosan that can be used industrially is estimated to be about 2 million tons per year, which is an enormous biological resource following cellulose. Chitin, which is a raw material of chitosan, Shells of crustaceans, epidermis of insects, mushrooms, and natural polymeric substances present in the cell walls of fungi. Recently, chitin, chitosan and its derivatives have been widely used for the treatment of cholesterol-lowering activity in the body, inhibition of formation of decayed substances by intestinal bacteria, anticancer activity by the action of immunity enhancement and hyperactivity, blood pressure lowering and hypertension inhibiting action, And antimicrobial activity. As a result, research and development as a new physiologically functional new material has been progressing actively, and its application range is expanding. Chitin and chitosan are administered orally to animals with little toxicity, intestinal bacteria are improved, and they bind to chlorine ions or bile acids to excrete them to the outside of the body, thereby lowering serum cholesterol levels and exhibiting blood pressure lowering effects.

In the composition of the present invention, chitosan having a molecular weight of 100,000 to 1,000,000 and chitosan oligosaccharide having a molecular weight of 3,000 to 30,000 may be preferably used.

(4) Eucalyptol

Eucalyptol can be pickled in a tree called eucalyptus and body odor can be sampled by steam distillation. The efficacy of eucalyptol is antiviral action of bronchial and respiratory system such as rhinitis and cold due to its natural antimicrobial action, so it exerts its effect and relieves inflammation and improves mucosal condition.

If eucalyptol is used at high concentration in the blood, it can stimulate the kidneys. Do not use it in people with hypertension or epilepsy.

When the content of the extract is increased, the effect of removing the bad breath of the composition is increased, but the stability of the composition with time is deteriorated. Therefore, when the concentration exceeds 2.0% by weight, browning may occur during storage at room temperature. And less than 0.005% by weight, the bad breath removing effect can not be obtained.

(5) copper sulfate

Vitar pigment, used as a coloring agent for vegetables and fruits, such as storage products and kelp.

Lt; / RTI > Blue crystals, lumps or bluish white crystalline powder. It is soluble in water and slightly soluble in ethanol. The aqueous solution is blue and acidic during hydrolysis. When left in the air, it gradually becomes enriched, loses crystals and discolors to white. When heated, it becomes anhydrous at 25 ℃. Color is colorless and it becomes copper oxide when heated to 650 ℃. It is known that it acts on the cell walls of algae and fungi and exhibits antibacterial and antifungal properties.

(6) Xylitol

Xylitol can help relieve symptoms by stimulating salivation when patients with dry mouth develop dry mouth due to aging. At this time, xylitol should be kept in the oral cavity for a long period of time.

Xylitol inhibits the growth of hemolytic streptococci including Pneumoniae, and steadily ingesting xylitol inhibits the growth of pathogenic bacteria in the respiratory and digestive tracts. It is also effective in preventing childhood otitis media.

Hereinafter, the present invention will be described in detail.

Hereinafter, the present invention will be described in detail based on Examples and Experimental Examples, but the technical scope of the present invention is not limited by these Examples.

Preparation of the saliva composition

The composition was prepared according to the ingredients and contents shown in Table 1 below.

≪ Test Example 1 >

Fusobacterium nucleatum, Streptococcus mutans, Candida albicans, which causes oral mucosal infections, and Aspergillus flavus, one of the fungi that inhibit long - term stability, were used for the measurement of antibacterial activity.

2 ml of the test solution diluted from 1:20 to 1: 5120 in Example 1 and Comparative Examples 1 to 5 and 18 ml of blood agar medium (blood agar base + 5% final concentration blood) were placed in a 9 cm petri dish Lt; / RTI > Then, the test bacteria were inoculated and cultured in an anaerobic chamber at 37 DEG C for 96 hours. The maximum dilution ratio at which the test bacteria did not grow was measured by MID and the results are shown in Table 1 (using Bactron I. anaerobic chamber).

The results of Table 2 are summarized as follows. Comparing Example 1 with Comparative Examples 2 and 4, the antimicrobial activity against halophilic bacteria (Fusobacterium nucleatum, Streptococcus mutans) was in the case of different composition ratios at a weight ratio of 1: 1: 1 to the pine wood phononchide and chitosan solution This means that the effect is superior to the case where the amount of only one of pine wood phytoncide, chitosan aqueous solution and eucalyptol is increased. Also, as shown in Comparative Examples 4 and 5, the addition of C31G (equal equivalent mixture of decane PB and inclamin oxide) resulted in better overall antibacterial activity. Candida albicans strains causing oral mucosal infections (oral candidiasis) were excellent in Example 1 and Comparative Examples 2, 4, and 5. In particular, the weight ratio of Pinus densiflora to chitosan aqueous solution and eucalyptol was 1: 1: 1 (Example 1, Comparative Examples 4 and 5).

On the other hand, as to the strains of Aspergillus flavus showing long-term storage stability, as is apparent from the results of the comparison between Example 1 and Comparative Examples 1, 2, 3 and 4 and Comparative Examples 4 and 5, the addition of CuSO4.5H2O , And especially when P. pinonchide and Eucalyptol were formulated together (the effect of Example 10 was maximized, and also the antibacterial activity was also observed in Comparative Example 2).

This means that it is possible to obtain the required antimicrobial activity by adding excessive amount of P. sinensis. Since most of the essential oil of Pine Trees is insoluble in water, there is a problem in storage stability of a preparation such as layer separation due to temperature change when added in excess In order to prepare a composition using pure natural extracts, further studies are needed.

≪ Test Example 2 > Measurement of deodorizing effect

Blank of Example 1 and Comparative Examples 1, 2, 4, 6 and pine wood phytoncide, chitosan, eucalyptol and mint flavor-free fractions were prepared and prepared by referring to the results of the above antibacterial activity test The odor inhibitory effect on the saliva composition was measured as follows. Fifty men (15 males, 35 females) without dental caries were selected and 1.0 g of raw garlic was masticated. Five minutes later, the mouth was washed with water. Then, the initial degree of halitosis was measured by a halimeter, It is set to the initial value. The test group was divided into 5 groups (3 males and 7 females), and fingers were soaked for 2 minutes with the gauze prepared in Example 1 and Comparative Examples 1, 2, 3, and blank, The halitosis was measured by a halimeter, and the resultant value was compared with the initial value. The usage of Halimerter is as follows. Before the measurement, the mouth was closed for 2 minutes, and the breath of the choromone was allowed to be maintained. In the measurement, the straw was kept in the mouth for about 15 seconds while being put in the mouth for about 1.5 seconds. At this time, the straw was kept from touching the tongue, and the lips were maintained at about 3 to 4 mm wide. The values of the halitosis inhibition rate (average value of 10 persons) obtained by measuring the measured values (in ppb units) of the Halimerter obtained from the respective test subjects are shown in Table 3 below. The odor suppression rate calculation equation is as follows.

Bad breath suppression rate (%) = 100 x (final value - initial value) / initial value <

As shown in Table 3, the odor produced after raw garlic chewing showed a suppression rate of about 20% in Comparative Example Blank which contains no active ingredient. As shown in Comparative Examples 2, 3 and 6 in which the P. vannamei phononchide and chitosan aqueous solutions were separately added, the odor inhibition rate was increased, but compared with the effective three components (pine wood phytoncide, aqueous chitosan solution, eucalyptol) The effect is weak. On the other hand, Comparative Examples 2 and 3 also show that the inhibition of bad breath of P. vannamei phytoncide is better than that of chitosan aqueous solution. Therefore, it can be seen that when mixed with P. chinensis aqueous solution, eucalyptol and copper sulfate solution as a remover for bad breath inducing substances, the halitosis can be more effectively suppressed by the synergistic effect of each component.

Claims (3)

Wherein the composition comprises copper sulfate and copper sulfate. Wherein the composition contains a mixture of chopped essential oil (phytoncide) and water-soluble chitosan, a 1: 1 equivalent mixture of cocamidopropyl betaine and myristyl dimethylamine oxide (C31G), and eucalyptol. 0.01 to 2.0 wt% of a 1: 1 equivalent mixture (C31G) of cocamidopropyl betaine and misstyldimethylamine oxide (0.001 to 1.0 wt%), 0.01 to 1.0 wt% of water-soluble chitosan, 0.001 to 5.0 wt% And 0.001 to 0.1% of copper sulfate to exhibit a synergistic effect.