FI78832C - FOERFARANDE FOER FRAMSTAELLNING AV EN NY MUNVAORDS COMPOSITION FOER BEFRAEMJANDE AV ORAL HYGIEN. - Google Patents

Description

1 78832

The present invention relates to a process for the preparation of an oral care composition containing an antibacterial agent which promotes oral hygiene, regulates plaque formation, gingivitis and dental root canal degeneration. The composition is administered topically to the oral cavity as a mouthwash or tooth powder containing an effective amount of an anti-gingivitis agent, 1-imidazoyl-1- (p-chlorooxy) -3,3-dimethyl-2-butanone (Climbazole, Bayer).

Gingivitis and purulence are diseases that affect the supporting tissues of the teeth such as the gums, the membranes surrounding the dental cavity and the bones surrounding the tooth. The disease may initially be associated with persistent gum irritation caused by tooth plaque, food wedging, poor bite, violent occlusion, or chemical irritation.

Gums can be severely affected by plaque, a combination of bacteria and minerals found in the mouth. Plaque bacteria can secrete enzymes and endotoxins that can irritate the gums and cause gingivitis. As this process constantly irritates more gums, they tend to bleed, lose their stiffness and elasticity, become detached from the teeth, and detach from the pituitary pockets, where accumulations, secretions, bacteria, and toxins continue to accumulate. It is also possible for food to accumulate in these pockets and nourish increased bacterial growth and promote the production of endotoxins and degrading enzymes. The wet that is generated in this process is able to destroy the gingival and bone tissue. Bacteria have generally been found to be present in the active stages of root membrane degeneration. Organisms such as anaerobic gram negatives are commonly present and have been observed in both purulent leakage and surrounding tissue, and can be absorbed into the general system through lymphatic tissue or venous circulation.

2 78832 The progression of the wet inflammatory process usually begins with gingivitis at the edges of the gums, where the gums become more and more tender and sensitive and become flabby, inflamed and swollen. The root pockets come out and become inflamed. Effective control and prevention of gingivitis then offers hopes of avoiding other root membrane diseases.

Several materials have been proposed and used in the past to control oral diseases and disorders such as plaque, tartar, rust, caries, bad breath, and root canal diseases such as gingivitis and wet inflammation, but none of these have been entirely satisfactory. Compositions containing anti-inflammatory agents that reduce the symptoms of edema, bleeding and inflammation associated with gingivitis by preventing the formation of dental rust and / or resisting the formation of tartar include, for example, imidazole such as histadine or histamine described in U.S. Patent 3,497,591, U.S. Patent 3,523,154 described dichloro-2-guanidino-benzimidazole, carrageenan described in U.S. Patent 4,029,760, a mixture of tranexamic acid and folic acid described in U.S. Patent 4,272,512, and tannic acid described in U.S. Patent 4,273,758. None of these substances are antimicrobial.

U.S. Patent 3,577,520 also discloses a 5,5-diaryl, 2,4-imidazolidinedione tooth powder composition for the treatment of wet inflammation which acts to repair inflammatory damage adjacent to a tooth.

U.S. Patent 3,911,133 discloses an antibacterial composition effective against both gram-positive and gram-negative bacteria comprising an imidazole derivative, bis- (a quaternary salt of imidazole), which is useful in mouthwashes, toothpastes and tooth gels by preventing the formation of dental plaque. or dental inflammation.

U.S. Pat. No. 3,788,328 discloses imidazole derivatives having high antimicrobial activity against dermatophytes, yeasts, molds, biphasic fungi and gram-positive chefs, which are useful as additives in oral hygiene products such as toothpastes and mouthwashes. as well as inflammations in general.

It is also known in the art that certain grem-negative organisms such as Bacteriodes asaccharolyticus or Bacteriodes gingivalis are associated with adult tooth root membrane degeneration. By eliminating these and other gram-negative anaerobes from plaque attached to gingival tissues, effective control and prevention of root canal diseases can be achieved.

Accordingly, Listgarton et al., In J. Periodont. Res. .14: 65-75 (1979), have shown that systemically administered metronidazole

CH0CH0OH

I 2 2

OF

N0_ —S CH, i Γ

--OF

causes the elimination of said gram-negative anaerobes from plaque. This was demonstrated by Heijl and Lindhe in J. Clinical Periodontology, §_t 197-209 (1979), which demonstrated that metronidazole is effective in reducing plaque and gingivitis corrosion in dogs, and Loesche et al. in the J. of Clinical Periodontology, 8: 29-44 (1981), which has shown that metronidazole is effective in reducing the amount of anaerobic B. asaccharolyticus from plaque removed from the gingival pockets, thereby substantially reducing pocket depth and significantly improving pocket adhesion. However, metronidazole, sold under the name Flagyl, is a carcinogen (Physician Reference Handbook p. 1761) and cannot be used safely.

4,78832

It has now been found that the second imidazole derivative is also effective against said gram-negative anaerobic organisms and is not carcinogenic or mutagenic and can be administered topically to the oral cavity in the treatment of gingivitis. This derivative is 1-imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone.

Imidazoyl ketones such as 1-imidazoyl-1- (4-chlorophenoxy) -3,3-dimethyl-2-butanone are described in U.S. Patents 3,812,142 and 3,903,287 as antifungal agents for use in pharmaceutical compositions such as pastes, gels, ointments. in aqueous and non-aqueous suspensions. Their action against pathogenic protozoa against gram-positive and negative bacteria such as Staphylococci and Escherichia coli has also been taken into account.

GB patent 1,502,144 and the corresponding DE patent 2,430,039 disclose compositions for the treatment of hair and skin which are effective against Pityrosporum ovale and which contain, as an antifungal agent, imidazoyl ketone dispersed in a dermally approved carrier containing a detergent compound. The compositions are in the form of creams, aerosols, powders and liquids. DE patent 2,600,800 discloses 1-imidazoyl-1- (4-chlorophenoxy) -3,3-dimethyl-2-butanone as a fungicidal composition, either dry or dispersed in water, as a water-in-oil or oil-in-water emulsion, or as a spray to protect the patch surface, dispersion paints, wall paper, brick surfaces, paints, adhesives, bitumen, furniture, leather, shower curtains, textiles, carpets, wood and paper against a variety of pathogenic fungi, molds and bacteria. However, no mention is made of the organisms Bacteroides asaccharolyticus or gingivalis, specific anaerobic gram-negative organisms found in connection with gingivitis. DE patent 2,700,806 also mentions a mixture of imidazoyl ketone fungicide and quaternary ammonium bactericide for use in the protection of materials such as paints, adhesives, bitumen, cellulose, paper, textiles, leather and wood.

Il 5 78832

Although the art is known in the art as an antifungal agent for this imidazoyl ketone and its use for pharmaceutical purposes, especially in hair and skin care compositions, its use in dental preparations or its efficacy against certain non-mentioned gram-negative anaerobic organisms found in gingivitis and root canal degeneration.

It has now been found that a water-insoluble imidazoyl ketone, 1-imidazoyl-1- (p-chlorophenoxy> -3,3-dimethyl-2-butanone), is selectively effective against certain anaerobic gram-negative organisms found in gingivitis when administered topically to the desired gum.

Accordingly, it is a main object of the present invention to provide a process for preparing an oral care composition containing the above-mentioned water-insoluble imidazoyl ketone as an anti-gingivitis agent solubilized in an orally useful excipient.

The present invention therefore relates to a process for the preparation of a novel oral care composition for promoting oral hygiene in the form of a toothpaste, gel, ointment, mouthwash or chewing gum, which process is characterized by mixing an effective amount of about 0.1 to 5% by weight of the composition. , a water-insoluble anti-gingivitis agent, 1-imidazoyl-1- <p-chlorophenoxy> -3,3-dimethyl-2-butanone, with a nonionic compound which is a surfactant containing a hydrophobic radical and about 10 to 80 hydrophilic units of weight-X polyoxyethylene long enough to effect dissolution, or a humectant which is polyoxyethylene glycol or polyoxypropylene glycol with a weight ratio of nonionic to anti-gingival agent of about 3: 1 to about 25: 1 with water and then the resulting mixture is mixed with water and with.

Preferably, the nonionic surfactant is a substance containing a hydrophobic radical having a higher fatty acid radical of 10 to 20 carbon atoms, polyoxypropylene, a monohigher granular acid ester of hexitanium or a fatty acid amide; and a hydrophilic group of polyoxyethylene sufficient for solubilization. The oral excipient used may be a liquid such as mouthwash or rinse, a solid such as chewing gum or tooth powder, paste or ointment. Oral care compositions are non-toxic and have a pH of about 5-7.5.

Mouthwash having a pH of about 5-7.5 is an aqueous alcohol excipient containing about 1-5 weight percent X of a nonionic surfactant selected from the group consisting of ethylene oxide block polymers, blended polymers of propylene oxide and ethylene oxide, polyoxyethylene hexane monosaccharides. esters containing 10 to 80 moles of ethylene oxide per mole, and mono- and diethanolamides of higher fatty acids and mixtures thereof.

The surfactant contains about 10 to 80 weight percent X of polyoxyethylene hydrophilic units and hydrophobic radicals such as polyoxypropylene, preferably having a molecular weight of 3250, as a blend polymer of propylene oxide and ethylene oxide. The ratio of soluble to imidazole is about 1: 1: 1: preferably about 3: 1-25: 1. Gelation occurs in a ratio greater than 25: 1.

The toothpaste, which also has a pH of about 5-7.5, comprises a dentifrice-acceptable abrasive and a liquid excipient containing water and about 20-40% by weight of a nonionic humectant, including at least one humectant which is polyethylene glycol or polypropylene glycol. Part of the humectant may be replaced by glycerin, sorbitol or mannitol provided that said anti-inflammatory agent is dissolved.

The anti-gingivitis agent used in this invention is 1-imidazoyl- (p-chlorophenoxy) -3,3-dimethyl-2-butanone having the formula:

Cl -V O-CH-COC (CHo) o

I II

_-OF

and prepared by reacting 1-bromo-1- <4-chlorophenoxy> -3,3-dimethyl-2-butanone with imidazole li 7,78832 dissolved in acetonitrile as described in U.S. Patents 3,812,142 and 3,903,287, which form part of this explanation. This imidazoyl ketone is a water-insoluble crystalline powder with a melting point of 94.5-97.8 ° C supplied by Bayer Company under the name Climbazole. Due to the water insolubility of this imidazoyl compound, it should first be solubilized with a nonionic compound before adding ionic materials to the aqueous medium.

It has surprisingly been found that this antibacterial compound, when added to excipients used in oral care products, is not only effective against certain anaerobic organisms associated with dental root canal disease, but also significantly cures the disease when administered topically as well as reduces the symptoms of gingivitis associated with gingival degeneration. The minimum concentration (MIC) required to kill Bacteroides asaccharolyticus (Forsyth strain), determined according to the procedure of Walker et al. (Antimicrobial and Chemoterapy, Vol. 16, pp. 452-457, 1979), is between 7.8-31, 2 micrograms per milliliter. The MIC value for B. gingivalis is 25 micrograms per ml. The MIC value for B. gracilis and Fusobacterium, for other gram-negative organisms, is both greater than 50; and the MIC value for the gram-positive organism Actinomyces viscous is 125 for the aerobic strain and 250 for the anaerobic strain. This clearly demonstrates the selectivity of the antibacterial activity of a particular imidazole compound used herein as an anti-gingivitis agent.

Evaluation of oral care products for 30 beagles in a 10-week trial using 0.3% Climbazole-containing mouthwash clearly demonstrated its superior efficacy in the treatment of gingivitis. In the procedure used, both soft and hard deposits were completely removed from the tooth, after which the dogs were kept on a soft diet for six weeks, thus allowing the development of gingivitis. The dentition was then treated with the test solution twice a day for five days a week for 8,78832 for about 15 seconds on each side of the mouth. The animals were examined and the degree of inflammation was assessed according to a scale of 0-3.

O = no inflammation. 1 = mild local swelling and redness at the edge of the gum, no bleeding with a light finger press. 2 = moderate swelling and redness at the edge of the gum, bleeding with a light finger press. 3 = severe swelling and wound formation at the edge of the gum and gums and bleeding without finger pressure. Placebo and 0.5% metronidazole wash were used as negative and positive controls, respectively. The results are summarized in Table 1.

Table 1 Treatment Initial 6 weeks 10 weeks _ firing units _ _

Servings 0 1 2 3 0 1 2 3 0 1 2 3

Placebo rinse 9,583 8 - - 569 31 - - 528 72 0.5% Metron-diazole rinse 13,578 9 - - 572 28 - - 576 24 0.3%

Climbazole 11,589 - - 579 21 - - 578 22

Compared to placebo, both Metronidazole and Climbazole rinses significantly reduced the development of gingivitis units 2. However, a smaller amount (0.3%) of Climbazole showed the same efficacy against gingivitis as a higher amount (0.5%) of Metronidazole.

However, although metronidazole, when administered systemically, is effective against certain gram-negative microorganisms present in root membrane disease, as fully described in the prior art description, it does not function as well when administered topically. The reason for said poor results is the absence of suitable hydrophobic groups in its structural formula, which is necessary for its penetration into the gingival tissue. Climbazole, on the other hand, has a free hydrophobic group (p-chlorophenoxy) -3,3-dimethyl-2-butanone), which

II

9,78832 provides good penetration into tissues in which the destructive process of tooth root membrane degeneration occurs, while maintaining an effective concentration of antibacterial agent to reduce the bacterial count of gram-negative microorganisms present in this disease. In addition, metronidazole is mutagenic due to its nitro group while Climbazole is not mutagenic in mutagenicity tests because it lacks a nitro group as can be seen from the structural formula below:

Climbazole Metronidazole

Cl 2 (^) ^ - O-CH-COC (CH 3) 3 CH 2 'CH 2 * OH

NO -CH.,

Cl 2 L_T 3 The oral treatment composition of this invention may be a liquid such as a mouthwash or lotion. In such preparations, the excipient is typically an aqueous alcohol mixture. In general, the water: alcohol weight ratio is in the range of 1: 1 to 20: 1, preferably 3: 1 to 20: 1. The amount of alcohol is preferably about 20-40% by weight of the excipient. The total amount of aqueous alcohol mixture in this type of preparation is typically in the range of 70-98% by weight of the preparation. The pH of such a liquid and other preparations of the invention is generally in the range of about 5-7.5.

An essential component in liquid oral care preparations is about 1-5% by weight of a nonionic surfactant containing 10-80% by weight of hydrophilic units of polyoxyethylene as well as hydrophobic polyoxypropylene or a higher fatty acid, its ester or amide to dissolve water-insoluble Climbazole in water-soluble Climbazole.

Suitable nonionic surfactants are ethylene oxide block polymers, blended polymers of propylene oxide and ethylene oxide, mono-higher fatty acid esters of polyoxyethylenehexitanium / having 10 to 20 carbon atoms in the acyl moiety and 4 to 100, preferably 10 to 80 moles per ethylene oxide. Hexitanium is preferably sorbitan, although mannitan and other hexitans are also frequently used, the higher fatty acyl has 10-16 or 20 carbon atoms, preferably 12-16 or 18 carbon atoms, and most preferably about 12 carbon atoms, and the number of ethoxy is 15-80, often preferably about 20. Highly preferred is the product of ICI, sold under the tradename Tween 20 and also known as Polysorbate 20, which is polyoxyethylene (20) sorbitan monolaurate.

Similar useful products are sold with similar identifications, such as Tween 40, 60, 65, and 80, all of which are nonionic surfactants in which the fatty acyl is palmitoyl, stearyl, or oleoyl, and the number of moles of ethylene oxide per mole is about 20. however, diethylene sorbitan monolaurate is the most popular. Polyoxyethylene (80) sorbane monolaurate can be used instead of said polysorbate 20.

Other suitable nonionic surfactants include mono- and diethanolamides of higher fatty acids having 10 to 18 carbon atoms in the acyl group, such as coconut monoethanolamide, coconut diethanolamide, lauryl-myristyl-diethanolamide, lauryl monoethanolamide, or combinations thereof.

The present oral care products may be substantially pasty in nature such as toothpaste or toothpaste. The excipient for such pasty oral care preparations contains an abrasive material. Examples of the abrasive material are water-insoluble sodium metaphosphate, potassium metaphosphate, tri-calcium phosphate, calcium pyrophosphate, magnesium, trimagnesiumfosfaatti, calcium, aluminum, hydrated aluminum hydroxide, aluminum silicate, zirconium silicate, silikabento rivet, crystalline silica, having a particle size up to 5 microns, silica gel, amorphous alkali metal alumino-complex , hydrated aluminum, dicalcium phosphate and mixtures thereof.

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When using visually clear gels, highly useful abrasive powders include colloidal silica, such as those sold under the tradename SYLOID Syloid 72 and Syloid 74 or under the tradename SANTOCEL Santocel 100, and alkali-metal aluminosilicate complexes due to their proximity system (including water and / or humidifier) refractive properties commonly used in tooth powders.

The abrasive material is usually present in about 10-99% by weight of the oral care preparation. It is usually present in toothpaste in about 10-75%.

In toothpaste, the liquid excipient typically comprises water and a humectant in an amount of about 10-90% by weight of the preparation. The essential component of the toothpaste and toothpaste is about 20-40% by weight of a nonionic humectant, including at least one humectant selected from the group consisting of polyethylene glycol and polypropylene glycol, to dissolve the water-insoluble Climbazole in the aqueous excipient. Glycerin, sorbitol and mannitol may be replaced by a portion of a humectant, provided that said imidazole compound is solubilized in polyoxyethylene or polyoxypropylene glycol.

A gelling agent such as natural or synthetic gums or gummy materials, typically carrageenan, sodium methylcellulose, methylcellulose, hydroxyethylcellulose, gum tragacanth, polyvinylpyrrolidino, starch and hydroxypropylmethylcellulose up to 0.5% by weight, is usually present in the toothpaste. In toothpaste and gel, the liquid and solid substances are in such a ratio that they form a creamy or gel-like mass which can be extruded from a pressure vessel or a compressible, for example aluminum or tin tube.

The oral care composition of this invention may contain a non-soap synthetic sufficiently water-soluble organic anionic or nonionic surfactant in concentrations generally in the range of about 1 to 5% by weight to promote wetting, surfactant, and foaming properties. U.S. Patent 4,041,149 discloses such suitable surfactants in column 4, lines 31-38, column 8, lines 30-68, and column 9, lines 1-12, which are incorporated herein by reference only.

The antibacterial oral compositions of this invention may optionally contain a fluorine-containing compound, including inorganic fluoride salts such as soluble alkali metal, alkaline earth metal and heavy metal salts, for example sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, copper fluoride, such as copper fluoride, zinc fluoride, tin fluoride such as tin (IV) fluoride or tin (II) chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- or difluorophosphate and sodium fluoride. Preferred are alkali metal and tin fluorides such as sodium and tin (II) fluorides, sodium monofluorophosphate and mixtures thereof.

The amount of fluorine-containing compound depends to some extent on the type of compound, its solubility and the type of oral care preparation, but the amount must be non-toxic. In a solid oral care product such as toothpaste or chewing gum, an amount of such compound of up to about 1% by weight of the preparation is considered satisfactory. Any minimum amount of such a compound may be used, but it is preferred to use sufficient compound to release about 0.005-1%, and preferably about 0.1% fluoride ions. In the case of alkali metal fluorides and tin fluoride, this component is typically present up to 2% by weight based on the weight of the preparation, and preferably about 0.05-1%. In the case of sodium monofluorophosphate, the compound may be present up to 7.6%, more typically about 0.76%.

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Several other materials can be combined with the oral care products of this invention that do not adversely affect the properties of the composition. Such materials include sweeteners (e.g., saccharin, sucrose, lactose, maltose, sorbitol, etc.), spice oils (e.g., green mint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon). , lemon, orange oils, etc.), coloring or bleaching agents (e.g., titanium dioxide), preservatives (e.g., sodium benzoate), and the like. Smaller amounts, up to a total of 5%, and preferably 0.01-3% by weight, of these substances may be added to the oral care product.

The present oral care products are readily prepared by simple mixing methods from readily available components. However, it is essential that the imidazoyl compound be first mixed with the nonionic compound before being added to an excipient that typically contains water.

For example, a mouthwash or lotion can be prepared by first solubilizing the imidazole compound by emulsifying it in a nonionic surfactant before adding it to an aqueous agent or an alcohol-water excipient. Other ingredients such as spice, sweetener, etc. may be added to the aqueous excipient before or after the addition of the dissolved imidazole.

Toothpaste can be prepared by first adding an imidazole compound to a nonionic humectant and dissolving it, and then adding a thickener such as carboxymethylcellulose to form a gel, followed by the addition of an abrasive, water and other ingredients. The order of the various ingredients may vary, except that the imidazole compound is first dissolved in a nonionic humectant before being added to the aqueous component.

In practice, an oral care product of the present invention such as a mouthwash or toothpaste containing 1-imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone as an anti-dental agent to improve oral hygiene is regularly administered to the tooth enamel about 1-3 times. per day at a pH of about 5-7.5.

The following limited examples further illustrate the nature of the present invention, but should not be construed as limiting the invention. All amounts and proportions set forth herein and in the claims are by weight unless otherwise indicated.

Example 1

Mouthwash

Suuvesiliuos:

Alcohol = 25%

Climbazole = 0.3%

Spices (K-91-3863) = 0.22 * Pluronic F108 = 3.0

Glycerin = 25

Sodium saccharin = 0.03%

Water to a total of 100% * A copolymer of about 80% by weight polyoxyethylene and about 20% by weight pc-lyoxypropylene having a polyoxypropylene radical molecular weight of 3250 was obtained from BASF Wyandotte Company.

Climbazole was mixed with Pluronic until the mixture was homogeneous and clear before being added to an aqueous alcohol excipient containing glycerin, spice and sodium saccharin.

The obtained product is effective in controlling gingivitis and in the treatment of tooth root membrane decay and can be used to improve oral hygiene by simple means applied regularly 1-3 times a day to the oral cavity.

15 78832 The unexpectedly good anti-gingival activity of this product is shown in Table 1, where the mouthwash of Example 1 was used as a test solution. This product also has antibacterial properties against the organisms Bacteroides assaccharolyticus and B. gingivalis.

Example 2 Toothpaste

Ingredients Percent Grams H 2 O 31.3 156.5

Na - Benzoate 0.5 2.5

Na - Saccharin 0.2 1.0

Polyethylene glycol 600 ^ - 25.0 125

Climbazole 1.0 5.0

Carboxymethylcellulose 1.5 7.5

Syloid-2442 3.0 15.0

Zeo-493 35.0 175

Sodium lauryl sulphate 1.5 7.5

Spice 1.0 5.0 3H (OCH2CH2) nOH, where n is an integer from 10 to 14, preferably from 12.5 to 14 and has a molecular weight of 570 to 630 2 colloidal silica 3 sodium aluminosilicate (silica with 1% aluminum added) manufacturer Huber Co.

Climbazole is premixed with polyethylene glycol before being added to carboxymethylcellulose to form a gel. To this gel are added by stirring Syloid, Zeo, sodium lauryl sulfate, spice, butter, benzoate and saccharin. Benzoate and saccharin can be dissolved in water before mixing with other ingredients. Likewise, Zeo, spice and sodium lauryl sulfate can be premixed before being added to the gel.

This product also has similar good antimicrobial anti-gingivitis properties.

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Other conventional components may be replaced or added as previously described. For example, hydrated aluminum or water-insoluble metaphosphate or dicalcium phosphate dihydrate and other abrasives can be completely and partially replaced with alkali metal aluminosilicate (Zeo) or colloidal silica (Syloid). Likewise, other nonionic surfactants can be replaced by a copolymer of propylene oxide and ethylene oxide (Pluronic) such as mono-higher fatty acid esters of polyoxyethylenehexitanium.

It is to be understood that the above detailed description is given by way of illustration only and that various modifications may be made without departing from the spirit of the invention. The above "summary" is for the convenience of those skilled in the art only and does not define the scope of the invention.

Il

Claims (6)

A process for preparing a new mouthwash composition in the form of toothpaste, gel, cream, mouthwash or chewing gum to promote oral hygiene, characterized by mixing an effective amount, soro is about 0.1-5 X of the composition. weight, of the water-insoluble antigen giving agent 1-imidazoy1-1- (chlorophenoxy) -3,3-dimethyl-2-butanone with a nonionic compound consisting of a surfactant containing a hydrophobic radical and about 10-80 weight-X hydrophilic radicals of polyoxyethylene of sufficient length to effect solubilization or a humectant consisting of polyoxyethylene glycol or polyoxypropylene glycol, the weight ratio of the nonionic agent to the antigenic agent being about 3: 1 - about 25: 1, and already mixed the obtained mixture with an aqueous oral aid. Process according to claim 1, characterized in that the pH of the composition is adjusted to a value of about 5-7.5. Method according to claim 1 or 2, characterized in that a nonionic surfactant consisting of a segment polymer of propylene oxide and ethylene oxide is used, a mono-right fatty acid ester of polyoxyethylene hexite containing 10-80 moles of ethylene oxide per mole, or a mixture thereof. Method according to any of claims 1-3, characterized in that as a nonionic surfactant, a compound 9 containing a hydrophobic polyoxypropylene radical and hydrophilic polyoxyethylene radicals is used, the weight ratio between the hydrophilic radicals and the hydrophobic radical being about 4: 1. . n