WO2000066070A2

WO2000066070A2 - Utilization of nanoscalar, antimicrobial active ingredients in oral and/or dental hygiene

Info

Publication number: WO2000066070A2
Application number: PCT/EP2000/003660
Authority: WO
Inventors: Christine Schröder; Hans Dolhaine; Peter Wülknitz; Hans Theo Leinen; Dorothea Gregori
Original assignee: Henkel Kommanditgesellschaft Auf Aktien
Priority date: 1999-04-30
Filing date: 2000-04-22
Publication date: 2000-11-09
Also published as: WO2000066070A3; DE19919770A1; AU4554900A

Abstract

The invention relates to the utilization of nanoscalar, antimicrobial active ingredients with an average particle size in the region of between 5 and 500 nm, for producing oral and/or dental hygiene products, in particular, for producing toothpastes or gels for cleaning the teeth. In contrast to active ingredient forms described in prior art, the especially fine distribution of the particles allows the active ingredients to be more easily integrated into formulations and to be more effective.

Description

"Use of nanoscale antimicrobial agents in oral and / or dental care"

The invention relates to the use of antimicrobial agents in nanoscale form for the manufacture of oral and / or dental care products.

Bacterial plaque is considered to be the main cause of tooth decay and tooth bed inflammation. For this reason, antimicrobial agents such as z. B. cetylpyridinium chloride, chlorhexidine, hexetidine, domiphen chloride, triclosan and sodium benzoate. Clinical studies show that such formulations can inhibit plaque formation and growth to a limited extent. From EP 0262587 salicylamides are known which are effective against gram-positive bacteria and, because of their potency and their advantageous spectrum of action, have been proposed as antiplaque agents for agents for oral and dental care, for example mouthwashes and toothpastes. Because of their poor solubility, these salicylamides are so difficult to incorporate into the formulations that are used that no antibacterial effects sufficient for practical use can be achieved.

Nanoscale substances are substances whose particle diameter in the direction of the greatest expansion of the particles is less than 1000 nm (nanometers). In the present document, the term "nanoparticulate" is used synonymously with the term "nanoscale".

Nanoscale active ingredients are described in the literature in particular as a means of achieving a controlled release of the active ingredient over a longer period of time. For example, WO 98/14174 discloses nanoparticles for parenteral therapeutic use which consist of a pharmacologically active substance encapsulated in a shell made of a biodegradable polymer. Examples of pharmacologically active substances include antibacterial substances such as chloramphenicol and vancomycin and antimicrobial substances such as penicillins and cephalosporins.

^'Sche antimicrobial products containing nanoscale Schiff bases of aromatic aldehydes are known from DE 4402103, which describes the use of these products for long-lasting antimicrobial bielien finishing of textiles.

Application CA 2,111,523 describes disinfectants which, in addition to other constituents, also contain surface-modified nanoparticulate antimicrobial active ingredients. A disinfectant cleaner formulation is given as an example. The application CA 2,111, 522 describes compositions with long-lasting germicidal activity which contain surface-modified nanoparticulate antimicrobial agents. Disinfectants for surface treatment which provide permanent antimicrobial films on the treated surface are described as applications of these compositions.

However, the prior art provides no evidence that nanoparticulate antimicrobial substances can advantageously be used as active ingredients in the field of oral and dental care. On the one hand, it is known to the person skilled in the art that antimicrobial active ingredients both, for. B. in the field of surface disinfection as well as in the field of oral and dental care. On the other hand, however, he is also aware that the type of application as well as the requirements for the potency, the spectrum of action and the formulation of the active ingredients in the different areas of application are so different that the knowledge gained in one area of application does not imply another area of application in an obvious manner can be transferred. In practice, the problem frequently arises with antimicrobial active substances, in particular with poorly water-soluble active substances, that these active substances are difficult to incorporate into formulations for oral and / or dental care and that the formulations obtained show an unsatisfactory antimicrobial effect.

In addition, there is a need among consumers for oral and / or dental care products which manage without reduced antimicrobial activity with reduced use concentrations of the active ingredient and thus offer health, economic and / or ecological advantages.

It was therefore an object of the invention to enable the production of oral and / or dental care products using such antimicrobial agents which, because of their poor solubility, cannot be incorporated in sufficient concentrations in oral and / or dental care products in conventional ways.

Another object of the invention was to provide oral and / or dental care products with an antimicrobial activity sufficient for the application and at the same time a reduced content of antimicrobial active substances.

The object was achieved in that the antimicrobial active ingredients in the form of nanoparticles with a particle diameter in the range from 5 to 500 nm, preferably from 10 to 150 nm, are used to produce the oral and / or dental care products.

The invention therefore relates to the use of nanoscale antimicrobial active ingredients with a particle diameter in the range from 5 to 500 nm, preferably from 10 to 150 nm, for the production of oral and / or dental care products, in particular toothpastes or toothbrush gels. Surprisingly, it was found that the antimicrobial active ingredients in nanoparticulate form are not only easier to incorporate into formulations of oral and / or dental care products, but that their effectiveness is also increasing. This means that when used with the same weight, the nanoparticulate active substance produces a stronger antimicrobial effect than the same active substance in a larger particle size.

The use of the antimicrobial active ingredients in nanoparticulate form is particularly noticeable if the active ingredients themselves are poorly water-soluble or if they are non-basic compounds which, accordingly, are not converted into readily water-soluble salts by the addition of acids can.

Accordingly, further embodiments of the invention are directed to antimicrobial active ingredients which are poorly water-soluble and to those which are non-basic compounds.

The antimicrobial active substances according to the invention are preferably to be understood

4-hydroxybenzoic acid, its salts with alkali or alkaline earth metals or its esters with linear or branched alcohols with 1-10 C atoms

N- (4-chlorophenyl) -N ^' - (3,4 dichlorophenyl) urea

2,4,4 ^' -Trichlor-2 ^' -hydroxy-diphenyl ether

4-chloro-3,5-dimethylphenol

2,2'-methylene-bis (6-bromo-4-chlorophenol)

3-methyl-4- (1-methylethyl) phenol

2-benzyl-4-chlorophenol

3- (4-chlorophenoxy) -1, 2-propanediol

3-iodo-2-propynyl butyl carbamate

Vitamin A palmitate Thymol

Salicylic acid N-alkylamides, where the alkyl radicals contain 1-22 carbon atoms and can be linear or branched and their mixtures.

Saiicylic acid N-octylamide and / or salicylic acid N-decylamide are particularly preferred as antimicrobial active substances according to the invention.

The nanoscale active substances according to the invention consist of a discrete phase of the active substance, on the surface of which at least one surface-modifying substance is preferably adsorbed. Emulsifiers and / or protective colloids are particularly suitable as surface-modifying substances. The coating of the particles with emulsifiers and / or protective colloids means that there is no subsequent agglomeration of the particles.

Examples of suitable emulsifiers are nonionic surfactants from at least one of the following groups:

(1) Adducts of 2 to 30 moles of ethylene oxide and / or 0 to 5 moles of propylene oxide with linear fatty alcohols with 8 to 22 C atoms, with fatty acids with 12 to 22 C atoms and with alkylphenols with 8 to 15 C atoms in the Alkyl group;

(2) C ₁₂ fatty acid monoesters and diesters of adducts of 1 to 30 moles of ethylene oxide with glycerol;

(3) glycerol monoesters and diesters and sorbitan monoesters and diesters of saturated and unsaturated fatty acids having 6 to 22 carbon atoms and their ethylene oxide addition products;

(4) alkyl mono- and oligoglycosides with 8 to 22 carbon atoms in the alkyl radical and their ethoxylated analogs;

(5) adducts of 15 to 60 moles of ethylene oxide with castor oil and / or hardened castor oil; (6) polyol and in particular polyglycerol esters, such as polyglycerol polyricin oleate, polyglycerol poly-12-hydroxystearate or polyglycerol dimerate. Mixtures of compounds from several of these classes of substances are also suitable;

(7) adducts of 2 to 15 moles of ethylene oxide with castor oil and / or hardened castor oil;

(8) _{partial esters} based on linear, branched, unsaturated or saturated C _6/22 fatty acids, ricinoleic acid as well as 12-hydroxystearic acid and glycerin, polyglycerin, pentaerythritol, dipentaerythritol, sugar alcohols (e.g. sorbitol), sucrose, alkyl giucosides (e.g. methyl glucoside, Butyl glucoside, lauryl glucoside) and polyglucosides (eg cellulose);

(9) mono-, di- and trialkyl phosphates and mono-, di- and / or tri-PEG-alkyl phosphates and their salts;

(10) wool wax alcohols;

(11) polysiloxane-polyalkyl-polyether copolymers or corresponding derivatives;

(12) mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol according to DE-PS 1165574 and / or mixed esters of fatty acids with 6 to 22 carbon atoms, methyl glucose and polyols, preferably glycerol or polyglycerol and

(13) Polyalkylene glycols.

The adducts of ethylene oxide and / or of propylene oxide with fatty alcohols, fatty acids, alkylphenols, glycerol mono- and diesters as well as sorbitan mono- and diesters of fatty acids or with castor oil are known, commercially available products. These are mixtures of homologs, whose average degree of alkoxylation corresponds to the ratio of the amounts of ethylene oxide and / or propylene oxide and substrate with which the addition reaction is carried out. C _12/18 fatty acid _monoesters and diesters of adducts of ethylene oxide with glycerol are known from DE-PS 2024051 as refatting agents for cosmetic preparations. C _8/18 alkyl mono- and oligoglycosides, their preparation and their use are known from the prior art. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols with 8 to 18 carbon atoms. With regard to the glycoside residue, both monoglycosides in which a cyclic sugar residue is glycosidically bonded to the fatty alcohol and oligomeric glycosides with a degree of oligomerization of up to preferably about 8 are suitable. The degree of oligomerization is a statistical mean value which is based on a homolog distribution customary for such technical products.

Typical examples of anionic emulsifiers are soaps, alkyl benzene sulfonates, alkane sulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, α-methyl ester sulfonates, sulfo fatty acids, alkyl sulfates, fatty alcohol ether sulfates, glycerin ether sulfates, hydroxymischlyether ether sulfates, mono (ether) sulfate ethersulfates (mon) and dialkyl sulfosuccinates, mono- and dialkyl sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids and their salts, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, N-acyl amino acids such as, for example, acyl lactylate, acyl tartrates, acyl glasate fatty acid (vegetable acyl glutamate fatty acid), (acyl glutate fatty acid) and acyl glutoglucate fatty acids (acyl glutamate fatty acid), (acyl glutoglucosate acid) and vegetable acid sorbate (acyl glutamate fatty acid), (acyl glucosate fatty acid), (acyl glucosate fate), Wheat-based products) and alkyl (ether) phosphates. If the anionic ten-side contains polyglycol ether chains, these can have a conventional, but preferably a narrowed, homolog distribution.

Zwitterionic surfactants can also be used as emulsifiers. Zwitterionic surfactants are surface-active compounds that contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines such as the N-alkyl-N, N-dimethylammonium gycinate, for example trimethylammonium glycinate Cocoalkyldimethylammonium glycinate, N-acylamino-propyl-N, N-dimethylammonium glycinate, for example the cocoacylaminopropyldimethylammonium glycinate, and 2-alkyl-3-carboxylmethyl-3-hydroxyethyiimidazolines each having 8 to 18 C atoms in the alkyl or acyl group and the alkyl or acyl group Coconut acylaminoethyl hydroxyethyl carboxymethyl glycinate. The fatty acid amide derivative known under the CTFA name Cocamidopropyl Betaine is particularly preferred. Suitable emulsifiers are ampholytic surfactants. Ampholytic surfactants are surface-active compounds which, in addition to a C _8/18 alkyl or acyl group, contain at least one free amino group and at least one -COOH or -SO ₃ H group in the molecule and are capable of forming internal salts. Examples of suitable ampholytic surfactants are N-alkylglycine, N-alkylpropionic acid, N-alkylaminobutyric acid, N-alkyliminodipropionic acid, N-hydroxyethyl-N-alkylamidopropylglycine, N-alkyltaurine, N-alkyl sarcosine, 2-alkylaminopropionic acid and alkyiaminoacetic acid, each with about 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and C _12/18 acylsarcosine. In addition to the ampholytic emulsifiers, quaternary emulsifiers are also suitable, those of the ester quat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred. Typical examples of anionic emulsifiers are alkyl sulfates, alkyl ether sulfates and monoglyceride (ether) sulfates.

As a rule, the active ingredients and the emulsifiers are used in a weight ratio of 1: 100 to 100: 1, preferably 1:25 to 25: 1 and in particular 1:10 to 10: 1. Emulsifiers which are capable of forming microemulsions are particularly preferred.

Suitable protective colloids are, for example, gelatin, casein, gum arabic, lysalbic acid, starch, carboxymethyl cellulose or modified Carboxymethyl cellulose and polymers such as polyvinyl alcohols, polyvinyl pyrrolidones, polyalkylene glycols and polyacrylates.

A further subject of the invention is thus the use according to the invention of nanoscale antimicrobial active substances in which the nanoparticles are encased by one or more emulsifiers and / or protective colloids.

The nanoparticles according to the invention can be produced, for example, by

(a) introducing active substances into a liquid phase in which they are not soluble,

(b) the resulting mixture is heated above the melting point of the active ingredients,

(c) adding an effective amount of at least one emulsifier to the resulting oil phase and finally

(d) the emulsion cools below the melting point of the active ingredients. The invention therefore also relates to the use according to the invention of nanoscale antimicrobial active substances which are produced by this process.

Another method for producing nanoparticles by rapid relaxation of supercritical solutions (RESS) is, for example, from the article by S.Chihlar, M.Türk and K. Schaber in Proceedings World Congress on Particle Technology 3, Brighton, 1998 known. To prevent the nanoparticles from caking again, it is advisable to dissolve the starting materials in the presence of suitable protective colloids or emulsifiers and / or to relax the critical solutions in aqueous and / or alcoholic solutions of the protective colloids or emulsifiers or in cosmetic oils, which in turn can contain dissolved emulsifiers and / or protective colloids.

Another suitable method for producing the nanoscale particles is offered by the evaporation technology. Here the starting materials are first in - Kl ¬

a suitable organic solvent (e.g. alkanes, vegetable oils, ethers, esters, ketones, acetals and the like). The solutions are then added to water or another non-solvent, usually in the presence of a surface-active compound dissolved in them, so that the homogenization of the two immiscible solvents leads to precipitation of the nanoparticles preferably evaporates organic solvents. Instead of an aqueous solution, O / W emulsions or O / W microemulsions can also be used. The emulsifiers and protective colloids already explained at the beginning can be used as surface-active compounds. Another possibility for the production of nanoparticles is the so-called GAS process (Gas Anti Solvent Recrystallization). The process uses a highly compressed gas or supercritical fluid (e.g. carbon dioxide) as a non-solvent for the crystallization of solutes. The compressed gas phase is introduced into the primary solution of the starting materials and absorbed there, which increases the volume of the liquid, the solubility decreases and fine particles are separated out.

The PCA method (Precipitation with a Compressed Fluid Anti-Solvent) is similarly suitable. Here the primary solution of the starting materials is introduced into a supercritical fluid, whereby finely divided droplets form in which diffusion processes take place, so that the finest particles are precipitated. In the PGSS process (Particles from Gas Saturated Solutions), the starting materials are melted by injecting gas (e.g. carbon dioxide or propane). Pressure and temperature reach near or supercritical conditions. The gas phase dissolves in the solid and causes a lowering of the melting temperature, the viscosity and the surface tension. When expanding through a nozzle, cooling effects lead to the formation of very fine particles. The production processes listed for the nanoparticles according to the invention are only to be understood as examples and do not constitute any restriction.

The amount of the nanoscale compounds is chosen so that the concentration of the antimicrobial active ingredients contained in the nanoparticles is usually in the order of 0.001 to 5, preferably 0.01 to 2 and in particular 0.1 to 1% by weight, based on the preparations .

The oral and / or dental care products obtainable using the nanoscale antimicrobial active ingredients according to the invention can be in the form of toothpastes, gels, liquid toothpastes, tooth powders, mouthwashes or optionally also as chewing agents, for example chewing gum. However, they are preferably in the form of more or less flowable or plastic toothpastes, such as are used to clean the teeth using a toothbrush. Toothpastes or liquid toothpastes according to the invention contain a polishing agent, usually in an amount of 5 to 50% by weight, and a humectant, usually in an amount of 10 to 60% by weight. Suitable polishing agents are all friction bodies known for toothpastes, such as, for example, silica, aluminum hydroxide, aluminum oxide, calcium pyrophosphate, chalk, dicalcium phosphate dihydrate, sodium aluminum silicates, for example zeolite A, organic polymers, for example polymethacrylate, or mixtures of these friction bodies. The addition of a polishing agent, which itself has a restorative effect on lesions and open dental tubules, the dicalcium phosphate dihydrate, has proven to be particularly suitable. Dicalcium phosphate dihydrate (CaHPO ₄ 2H ₂ O) occurs naturally as brushite and is commercially available in suitable grain sizes from 1 to 50 μm.

A combination of is suitable as a carrier for the toothpastes according to the invention, which enables the setting of a suitable consistency for dosing from tubes, dispensing containers or flexible bottles on the basis of the combination of polishing agents according to the invention Humectant, binders and water. For example, glycerin, sorbitol, xylitol, propylene glycols, polyethylene glycols, in particular those with average molecular weights of 200-800, can be used as humectants. Natural and / or synthetic water-soluble polymers such as alginates, carragheenates, tragacanth, starch and starch ethers, cellulose ethers such as carboxymethyl cellulose (sodium salt), hydroxyethyl cellulose, methyl hydroxypropyl cellulose, guar, acacia gum, agar agar, xanthan gum, for example, serve as consistency regulators (or binders) -Gum, succinoglycan gum, locust bean gum, pectins, water-soluble carboxyvinyl polymers (eg Carbopol ^® types), polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycols, in particular those with molecular weights of 1,500-1,000,000.

Other substances that are suitable for viscosity control are e.g. Layered silicates such as Montmorillonite clays, colloidal thickening silicas such as Airgel silicas, pyrogenic silicas or finely ground precipitated silicas.

The viscosity of the toothpastes can also be set so low that they can be dosed from a flexible plastic bottle onto the toothbrush as a "liquid tooth cleaning agent" with a viscosity of 2,000 - 40,000 m-Pa-s (25 ° C) penetrate between the bristles but do not drip off the toothbrush. For this purpose, a combination of 0.1 to 1% by weight of xanthan gum and / or carboxymethyl cellulose and 0.01 to 5% by weight of a viscosity-stabilizing additive from the group of the cationic, zwitterionic or ampholytic nitrogen-containing additives is preferably suitable as a binder

Surfactants

- The hydroxypropyl-substituted hydrocolloids or

- The polyethylene glycol / polypropylene glycol copolymers with an average molecular weight of 1000 to 5000 or a combination of the compounds mentioned. Surface-active substances are also present in the toothpastes according to the invention to support the cleaning effect and, if desired, also to develop foam during tooth brushing and to stabilize the polishing body dispersion in the carrier in an amount of 0.1 to 5% by weight. Suitable surfactants are, for example, linear sodium alkyl sulfates with 12 to 18 carbon atoms in the alkyl group. These substances also have an enzyme-inhibiting effect on the bacterial metabolism of the plaque. Other suitable surfactants are alkali metal salts, preferably sodium salts of alkyl polyglycol ether sulfate with 12 to 16 carbon atoms in the linear alkyl group and 2 to 6 glycol ether groups in the molecule, of linear alkane (C- _| 2-C- _| 8) sulfonate

Sulfosuccinic acid monoalkyl (C- | 2-C <| 8) esters, of sulfated fatty acid monoglycerides, sulfated fatty acid alkanolamides,

Sulfoacetic acid alkyl (C ^ 2-C- | 6) ^_estem . Acyl sarcosines, acyl taurides and acyl isethionates with 8 - 18 C atoms each in the acyl group. Zwitterionic, ampholytic and nonionic surfactants are also suitable, for example oxethylates of fatty acid mono- and diglycerides, of fatty acid sorbitan esters and alkyl (oligo) glucosides. Other common toothpaste additives are

Sweeteners such as Saccharin sodium, sodium cyclamate, sucrose, lactose, maltose, fructose,

- flavors such as Peppermint oil, spearmint oil, eucalyptus oil, anise oil, fennel oil, caraway oil, menthyl acetate, cinnamaldehyde, anethole, vanillin, thymol and mixtures of these and other natural and synthetic flavors,

- pigments such as Titanium dioxide

- dyes

- buffer substances such as primary, secondary or tertiary alkali phosphates or citric acid / sodium citrate,

- Wound healing and anti-inflammatory substances such as allantoin, urea and azulene, chamomile active ingredients, acetylsalicylic acid derivatives. In mouthwashes, the carrier consists essentially of water, ethanol, essential oils, emulsifiers and solubilizers for the rest

Aroma components, taste corrections (e.g. sweetener) and, if necessary, astringent or invigorating drug extracts and, if necessary, colorants.

To produce the oral and / or dental care products according to the invention, the nanoscale antimicrobial active ingredients are known to those skilled in the art

Way mixed with the other recipe components.

The invention accordingly furthermore relates to oral and / or dental care compositions containing antimicrobial active ingredients, which are characterized in that the antimicrobial active ingredient in the form of nanoparticles with a

Particle diameter in the range from 5 to 500 nm, preferably from 10 to 150 nm, is incorporated.

Further refinements and / or further developments result from the

Subclaims.

Examples

The following examples are intended to explain the subject of the invention in more detail:

Example 1: Preparation of nanoscale salicylic acid-N-octylamide 0.5 g of salicylic acid-N-octylamide (mp. About 45 ° C.) were dissolved in 100 g of deionized water and the mixture was heated to about 50 ° C., a two-phase Mixture of water and amide phase formed. The latter was emulsified by adding 8.9 g of alkyl ether sulfate (Texapon® N 70, Henkel KGaA, Düsseldorf) to form a clear mixture. The successive transition of the oil phase into the transparent water / amide / emulsifier mixture can be seen as an indication of the formation of a microemulsion. With continuous stirring, the microemulsion was cooled to ambient temperature and then evaporated to dryness on a rotary evaporator, giving 9.4 g of the salicylic acid-N-octylamide included in the ether sulfate matrix in nanoparticulate form. With ten times the amount of water, the nanoparticles could be processed into a stable and transparent dispersion. In light scattering, the particles showed a maximum with a particle size of 120 nm when numerically weighted.

Example 2: Preparation of a nanoscale aqueous salicylic acid-N-octylamide dispersion

1.0 g of salicylic acid-N-octylamide (melting point approx. 45 ° C.) was mixed with 30 g of deionized water, 30 g of polydiol 400 (PEG-8) and 2 g of polyoxyethylene glycol fatty acid ester (Tagat S) with slow heating to 52 ° C. emulsified. 30 g of fatty acid amidoalkyl betaine (Tego Betain BL 215) were then added, a clear, stable dispersion being formed. The mixture was then allowed to cool to room temperature. 93 g of a transparent dispersion were obtained. In light scattering, the particles showed a maximum with a particle size of 15 nm when numerically weighted. O 00/66070

16 -

The following oral and / or dental care products were produced with the nanoscale salicylic acid-N-octylamide prepared according to Examples 1 and 2 (all figures in% by weight, based on the preparation):

Examples 3 to 6: toothpastes

O 00/66070

17

Examples 7.1 - 7.4: Liquid toothpastes

O 00/66070

18 -

Example 8: Mouthwash (ready to use)

The following commercial products were used:

(1) Polishing clay P10 finely weakly calcined clay (approx. 20% by weight gamma-aluminum oxide approx. 80% by weight alpha-aluminum oxide primary crystal size 0.5 - 1.5 μm)

(2) Tego ^® Betain BL 215 30% solution of cocoamidopropyl betaine in water

(3) Cremophor ^® RH 60 Hydr. Castor oil + 60 mol EO

(4) Plantaren 2000 alkyl- (C ₈ -C ₁₆ ) -oligo- (1, 4) -glucoside (50% solution in water) O 00/66070

19

Example 9: Effectiveness test of nanoscale salicylic acid N-octylamids

The antimicrobial activity of the nanoscale salicylic acid N-octylamide prepared according to Example 2 was tested in comparison with the salicylic acid N-octylamide known from the prior art and produced according to EP 0262587 using the liquid toothpaste formulations from Examples 7.2 and 7.3. Both formulations contain the same concentration of the active ingredient salicylic acid-N-octylamide. In parallel, the corresponding drug-free formulation from Example 7.4 was also checked as a blank value.

To determine the germicidal effectiveness of toothpastes, they were tested in a quantitative suspension test (modified DGHM method) in concentrations of 25, 50 and 100% over a period of 2, 5 and 15 minutes. Staphylococcus aureus (ATCC 6538), Streptococcus mutans (DSM 20523) and Actinomyces viscosus (DSM 43329) served as test strains.

The individual results are listed in the tables below. The reduction factors are given in logarithmic values. Due to the biological variance, especially in the case of very short test times, only reduction factors of at least 2 iog levels are considered a significant reduction.

a) Results with toothpaste from example 7.2:

Staphylococcus aureus ATCC 6538:

O 00/66070

20 -

Actinomyces viscosus DSM 43329

b) Results with toothpaste from Example 7.3:

Staphylococcus aureus ATCC 6538

O 00/66070

- 21

c) Results with toothpaste from example 7.4:

Staphylococcus aureus ATCC 6538

The results show that the toothpastes tested did not result in a significant reduction in the test strains Staphylococcus aureus and Streptococcus mutans under the chosen test conditions. Actinomyces viscosus, on the other hand, is reduced significantly more by the toothpaste 7.2 containing nanoparticles at an application concentration of 25% than by the comparison toothpaste 7.3.

The effectiveness of the salicylic acid octylamide in nanoparticle form is therefore significantly greater than that of the active substance in the form known from the prior art.

To determine the long-term antibacterial effect, the toothpastes were tested in liquid rows of inhibitors (modified DGHM method). O 00/66070

22

To this end, toothpastes diluted with water to different extents were added to the same amounts of bacterial suspensions with a defined germ content. After incubation for 72 hours at 37 ° C., a smear was made per culture tube on a solid nutrient medium and the growth was assessed.

+ Growth (+) reduced growth no growth O 00/66070

- 23 -

The MIC values were determined in accordance with the above table, whereby MIC (minimum inhibitory concentration) is to be understood as the concentration at which bacterial growth can no longer be detected. MIC values in% by weight toothpaste

Note on the table:

The bacterial suspension of Streptococcus mutans could not be adjusted to the bacterial count of 10 ⁸ CFU / ml in this test. A direct comparison of the MIC values with the other test strains is therefore not possible. For the inhibition of 10 ⁸ CFU / ml Streptococcus mutans, higher drug concentrations tend to be assumed.

MIC values in ppm salicylic acid-N-octylamide

The long-term antibacterial effect of salicylic acid N-octylamide was demonstrated in the liquid series of inhibitors. The toothpaste formulation 7.2 with nanoscale salicylic acid N-octylamide showed the greatest inhibitory effect. For the inhibition of the test strain Staphylococcus aureus, a concentration of> 10% was required even after the active ingredient-free formulation 7.4 had taken effect for 3 days. In this test, the toothpaste with salicylic acid-N-octylamide in the conventional form inhibited Staphylococcus aureus in a concentration of 5% (50 ppm active ingredient). The analog toothpaste with the nanoscale active ingredient, however, already showed the same effect in a 1% concentration (10 ppm active ingredient).

In the series of inhibitors against Actinomyces viscosus, the formulation with the nanoscale active ingredient proved to be twice as effective as that with the active ingredient in conventional form.

Claims

claims

1. Use of nanoscale antimicrobial agents with a particle diameter in the range from 5 to 500 nm for the manufacture of oral and / or dental care products.

2. Use according to claim 1, characterized in that the active ingredients are poorly water-soluble compounds.

3. Use according to claim 1, characterized in that the active ingredients are non-basic compounds

4. Use according to at least one of claims 1 to 3, characterized in that active substances are selected which are selected from the group formed by 4-hydroxybenzoic acid and its salts and esters, N- (4-chlorophenyl) -N ^' - (3,4 dichlorophenyl) urea, 2,4,4 ^' trichloro-2'-hydroxy-diphenyl ether, 4-chloro-3,5-dimethylphenol, 2,2 ^' methylene bis (6-bromo - 4-chlorophenol), 3-methyl-4- (1-methylethyl) phenol, 2-benzyl-4-chlorophenol, 3- (4-chlorophenoxy) -1, 2-propanediol, 3-iodo-2-propynyl butyl carbamate , Vitamin A palmitate, thymol, salicylic acid N-alkyl amides, and mixtures thereof.

5. Use according to at least one of claims 1 to 4, characterized in that salicylic acid-n-octylamide and / or salicylic acid-n-decylamide is used.

6. Use according to at least one of claims 1 to 5, characterized in that nanoscale active ingredients are used, which are obtained by (a) introducing active substances into a liquid phase in which they are not soluble,

(c) adding an effective amount of at least one emulsifier or protective colloid to the resulting oil phase and finally

(d) the emulsion cools below the melting point of the active ingredients

7. Use according to at least one of claims 1 to 6, characterized in that nanoparticles are used which are coated by one or more emulsifiers and / or protective colloids.

8. Use according to at least one of claims 1 to 7, characterized in that the nanoscale active ingredients are used in such amounts that the concentration of the antimicrobial active ingredients contained in the nanoparticles is 0.001 to 5% by weight, based on the preparations.

9. Use according to at least one of claims 1 to 8, characterized in that the nanoscale active ingredients are used for the production of toothpastes or toothbrush gels.

10. Antimicrobial agent containing oral and / or dental care product, characterized in that the antimicrobial agent is incorporated in the form of nanoparticles with a particle diameter in the range from 5 to 500 nm.