DE3043792A1 - Dental health compsn. contg. biotin antagonist - to inhibit growth of biotin dependent cariogenic microorganisms - Google Patents

Abstract

Dental health prod. is a toothpaste, toothpowder, mouthwash, chewing gum, confection, tooth-coating concentrate or sustained-release buccal tablet contg. enough biotin antagonist (I) to prevent biotin uptake by microorganisms which cause dental caries, plaque and acid formation. Pref. (I) is a biotin inactivator and/or a biotin antimetabolite. (I) inhibit biotin which is an essential growth factor for the oral bacteria, so interfere with their development. They have no significant effect on the biotin store in the body.

Description

The invention relates to dental care products that contain biotin

clotagonists for the purpose of inhibiting development and effects Contains caries-causing microorganisms in the human mouth.

The applicant has not received any previously used or described products of some kind known to have the task of maintaining the environment in the oral bacteria exist, in such a way to regulate and adjust that the Ability to take the necessary vitamins normally found in saliva are available to be used to the full.

The invention is based on the principle for the human Microorganisms present in the mouth, which are the cause of tooth decay, the availability of biotin, which is normally present in human saliva is to severely limit. It has been found that biotin is an essential nutrient for these microorganisms, and the biotin withdrawal is supposed to their development and consequently seriously limit their ability to produce tooth decay. This biotin withdrawal will achieved by removing biotin antagonists through various dentifrices in the human Mouth. It is an important and notable trait d <'r Invention that the biotin Antagorilsten produce their effects directly in the mini-ecosystem, that is present in the human mouth. Biotin in the body itself should are not adversely affected, and are of the order of magnitude in question Biotin antagonists are the possible effects on the total occurrence of biotin insignificant in the body.

For the explanation of this invention, let us first refer to the background the mechanism of tooth decay, the vitamin biotin and the needs of the Decay promoting microorganisms on this vitamin and on biotin antagonists Entries that are able to use the normal pathways of biotin uptake to block the harmful microorganisms.

The mechanism by which dental caries appears to be formed is based on a twofold effect: firstly, the formation of tartar on the Dental surfaces through the production of a type of microorganism, the polymer forms carbohydrate-based, e.g., dextrans; second, usually by one Another group of microorganisms is formed by the formation of acids, which is the cause the actual destruction of the integrity of the tooth structure.

The acid formers inhabit the tartar. The tartar offers this Bacteria not only have a protected and shielded environment, they can do so also provide them with nutrients. Furthermore, the tartar can hold back the acids, which are formed in close proximity to the tooth surface, then the probability that the acids are diluted or removed from the tooth surfaces by other liquids rinsed away in the mouth is lower.

The tartar is mainly based on sucrose polymers, and the microorganism most suspected of being responsible for its formation to be is Streptococcus mutans. This was made in 1924 by J.K. Clark reported (Brit. Jour. Exp. Path., Vol. 5, 141-147).

The most significant work on this subject was later by j. Carlsson crelist (Odont Revy 18 (1967) 55-74; loc. cit. 19 (1968) 137-160; loc. cit. 19, Suppl. 14 (1968) 1970 Carlsson attempted to meet the nutritional requirements of Sterptococcus muLans to be determined. Using a stallune called tJ ('2, the isolated from humans, he found that biotin is essential for growth (Caries Research, 4, 305-320, 1970).

The acid-producing microorganisms have similar needs. 1944 Niven (Jour. Bact., Vol. 47, 343-350) showed that of 21 strains of Streptococcus lactis, which were examined for their vitamin requirements, all use biotin for growth needed. In 1950, S.A. Koser and H.J.

Fisher found 26 strains of lactobacilli from human saliva and found that biotin was essential for the growth of all these strains (J.Dental Res., Volume 29, 760-773) While lactic acid is considered to be the most common acid for the Tooth decay is responsible (A.T. Brown in Present Knowledqe of Nutrition, 1976, published by Nutrition Foundation, p. 492) "because of the deminerali dosage of the enamel and cement of crown and root surface caries is "one can see the possible contribution of other acids, e.g. propionic acid, to this Do not completely exclude the effect. In this regard, E.A. Delwicke (J. Bact. 58 (1949) 395-398) that of 25 strains of Propionibacterium most biotin needed for growth.

Biotin is a vitamin that plays a role in the respiratory function of organisms Rollo plays, and seems to be needed by almost all life forms. Some Organisms are able to synthesize their own biotin while others received it from external sources. It is a coincidence that many of the microorganisms those involved in education of dental caries are involved, an external source of biotin. This results in a situation in which biotin depletion is exploited as an aid to inhibiting their development, and this is exactly what happens according to the invention. By following a way of life and diets that permanently block the absorption of biotin can affect the conditions unfavorable for both tartar and acid formation the resulting advantages for the health of the teeth.

Depletion of biotmin or withdrawal of biotin for the microorganisms that cause tooth decay in the mouth by using dentifrices that biotin antagonists in insert the mouth, brought out. There are two classes of biotin antagonists. The first class consists of the numerous so-called "biotin antimetabolites".

D: W: Woolley defines in his book "A Study of Antimetabolites", Wiley, 1952 Die Antimetaboliten als structural analogs antagonistic to metabolites ".

(Structural analoqa that are antagonistic to metabolites). The structural Similarity to the active metabolites is believed to be responsible for the attachment of the antimetabolite in locations that are normally receptive to the true metabolite are. This will block the sites, and at least the true metabolite will be temporarily prevented from coupling to the substrate. The coupling effect with either the metabolite or the antimetabolite is considered to be a reversible reaction, and it is assumed that the positions are available and then always filled anew will.

The question of which remedy is most likely to turn to an available one Strictly speaking, it is a matter of the ratio of the concentrations of metabolites and antimetabolites in the environment. At the same concentrations equal numbers of places are occupied by each. To achieve, that only 1% of the tunnels are occupied by an active metabolite, the ratio of the concentrations of antimetabolite to metabolite must be 99 to 1.

A considerable number of compounds are mentioned in the literature, which are biotin antimetabolites. Not all modifications of the biotin molecule result to antagonistic properties. For example, it is known by what is known as Oxybiotin Compound in which oxygen is substituted for the sulfur in the molecule, in some Filling still preserves vitamin activity.

In order to be able to illustrate the modifications which lead to the formation of Antimetabo - @@@ en, as shown below the structure of the original active biotin III eraios it turns out that empty valence bonds are bound to hydrogen.

Examples of biotin antimetabolites are: desthiobiotin, in which -S is substituted by 2H.

Biotinsulfone, in which S is substituted by SO2.

Aliphatic ureylsncyclohexyl acids in which S is substituted by 2 C. is, and derivatives with shorter side chains.

r) esLhiojsobiotin, in which S is substituted by 2 H and the geometric Has isomerism.

Aliphatic ureylenetrahydrofurylsulfonic acids in which S is through 0 and COOH are substituted by SO3H.

Homobiotin with the addition of -CH2- in the side chain.

Ureylsncyclohexylvaleric acid, in which one 1 5 atom and 4 carbon atoms containing five-ring is substituted by a 6-C ring.

Alpha-dehydrobiotin with a double bond in al position to the COOH group.

Alphamethylbiotin with a methyl residue on the carbon atom in the alpha position to the COOH-C group.

Alpha-methyldesthiobiotin with a methyl residue in the alpha position for COOH group and 2 Ii instead of S.

Oxybiotin with a side chain with 6 carbon atoms and an additional one C-; atom in the side chain and substitution of S by 0.

Oxybiotinsulfonic acid, in which S is substituted by 0 and COOH by SOO3H are.

The literature also mentions: nor-biotin bishomobiotin trishomobiotin Alphatic 4-imidazole acids 2-oxo-4-imidazolidine caproic acid thiazolidon benzyl thioether Hydrazides and semicarbazides of biotin bishydrazides of suberic acid and sebacic acid Methyl 1,3-acetyl-4-thiazolidine carboxylate 1,2. Propyl 3-acetyl-4-thiazolodine carboxylate methyl ester and its hydrazide 2-piperidone-6-carboxylic acid hydrazide gamma (2-carboxy-3-indolyl) -butyric acid hydrazide 2-imidazolidone-4-carboxylic acid hydrazide 2-imidazolidone-4-caproic acid hydrazide 2-imidazolidone-4-valeric acid hydrazide.

The choice of biotin antimetabolites for use for the purpose the invention is not as difficult as one can choose from the large number of possible antimetabolites suspect could. Bring compounds like the antibiotic thiazolidone dangers of the development of antibiotic-resistant bacterial strains with and are to be avoided. Compounds produced by those found in living organisms are very different can be switched off, especially with regard to that those that are very similar are available. Connections with such minor changes like the addition of a carbon atom in the side chain or through The unsaturation produced by eliminating egg from the side chain would be promising considered to be low toxicity candidates, but the most logical of all is that Desthiobiotin, as it is clearly a biotin precursor in some microorganisms, E.coli in particular has been detected.

There is a very strong possibility that any amounts from desthiobiotin, which are absorbed by humans, from the intestinal flora to formation be used by biotin, which in turn is absorbed by the human body can be. It has been proven that the body's biotin supply increases Partly through its normal intestinal flora.

The second class of biotin antagonists are the biotin inactivators, which combine with biotin in such a way that they rob it of its ability to act as a vitamin to be effective.

Examples of biotin activators in this class are avidin, the is present in the protein of birds and amphibians.

Streptavidin produced by Streptomyces species.

An avidin-like compound found in egg yolks. (H.W. Meslar et al., J. Biol. Chem. 253, no. 19, (1978) 6979-6982 and J.C. McGuire et al, Biochm. J.1-57 (2) (1.8.197 () 395-400.) A biotin-binding Protein found in chicken plasma (R.D. Mandella et al, Biochem J.175 (2) (1978)) 629-634) Avidin is the most abundant compound of this class and is the longest as well as the best known. It is a complex glycoprotein with a molecular weight of 68.00. It comes in egg white in an amount of 0.05% before. Each avidin molecule has four active sites where it attaches itself to biotin can bind. The bond formed between avidin and biotin is very strong. the Dissociation constant is 10-15 (N.M. Green, Nature, 217 (1968) 254). The combination causes the biotin to become incapable of being effective as a vitamin.

For the purposes of the invention, avidin is a member of choice the class of biotin-deactivating biotin antagonists.

When deciding which class of fliotin antagonists for the Purpose of exhausting the biotin supply available for the oral microflora It is important to note the different effects exerted by each one to investigate. If on the one hand a biotin activator like avidin is in sufficienton There is enough power to react with all of the available biotin The biotmin is completely inaccessible to the microflora. Avidin has a molecular weight of 68,000 and biotin has one of 244.3 and 1 mole of avidin with 4 ols of riotin reacts, the stoichiometric ratio of the reactants is 68,000 to 4 x 244, or 69.6 to 1. This can add up to 70 parts by weight of avidin per part by weight of biotin be rounded up. Solanqe at least 70 times as much avidin as biotin is present the latter is inactivated.

With a biotin antimetabolite in the ratio of 70 parts to 1 Part of biotin reduces the biotin activity to 1/70 of its normal value. this is undoubtedly a substantial decrease, if not a total decrease to practically zero.

If the concentration of the biotin antagonist example W ('i se between the applications qerinqer is supplied while biotin continues in the saliva the remaining relative effectiveness of the biotin antagonist changes depending on its type. With avidin, for example, there can be a decrease to half, i.e. with 35 parts of avidin per part of biotin only half of the biotin be inactivated. A reduction in the antimetabolite from 70 parts to 35 parts per part of biotin causes a change in biotin activity from 1/70 to 1/35 of its 7activity. The biotin antimetabolite therefore has advantages when the more ideal ratios to fall boginnen.

The calculations to be incorporated are based on the following examples Quantities of biotin antagonists based on data in "Biochemists'Handbook" by Cyril Long, edited by Van Nostrand, 1961.

The manual shows the following important information: Average flow rate of "resting" saliva: 30 ml / hour. Range: 2.5 to 110 ml / hour.

Moderate salivation under stimulation: 114 ml / hour. Area: 24 up to 288 ml / hour

Biotin content in saliva: about 0.8 yug / liter.

To ensure effectiveness in all applications, the Calculations of the concentrations of the biotin antagonist all at maximum Salivary flow rates and, consequently, maximum rates of release of biotin into the mouth. The constant supply of biotin to the oral cavity through saliva must by the nature of the treatment provided according to the invention Efforts must be counteracted, and to be truly effective, efforts must be tireless remain to block the access of the microflora to the necessary biotin. To this Various means are provided by the invention to enable an increased degree made available for the introduction of biotin antagonists into the oral cavity It concerns the following products: toothpaste and toothpowder rfundwaters chewing gum Mouth pills, confectionery and confectionery Concentrates containing teeth. Oral tablets with prolonged release of the active ingredient.

These various means are illustrated by the following examples of Illustrated formulations.

Dentifrices The dentifrices produced according to the invention can be formulated either as toothpastes or as tooth powder.

Toothpastes have the usual ingredients such as water, cleaning material, Humectants, surfactants or foaming agents and flavoring agents and can also contain compounds containing fluoride ions or tin (II) ions and other substances obvious to those skilled in the art; however, contain they especially and specifically biotin antagonists. Since some components like Avidin is subject to attack by microorganisms, it is expedient to use a preservative or a combination of preservatives, e.g.

Methyl and propyl p-hydroxybenzoates.

The applied concentrations of the biotin antagonist have the the following logical basis: The amount of saliva in the mouth is in the absence of stimulation rather surprisingly small, namely less than 10 ml, and more often around 4 to 6 ml. A biotin content of 0.8 Fg / liter of saliva would mean that at most 0.008 pg biotin would be present to counteract this through the process of tooth brushing were. With a 70 to 1 ratio of the biotin antagonist as the usage ratio this would require 0.56 µg biotin antagonist per purification.

A "stranq" of toothpaste that is usually applied to the brush weighs approximately 1 to 1.5 g.

Om to be certain, it is believed that the smaller mencie, i.e. 1 cl is used. In other words, for every gram of toothpaste should be 0.56 pg biotin antagonist or 56 lg per 100 g.

Because the action of the biotin antagonist while brushing your teeth is of very short duration and the surfaces to be treated are not all light are accessible, according to the invention is preferably a ten-fold excess supplied in the concentration of the biotin antagonist for reliable effectiveness, i.e. 560 pg / 100 g toothpaste.

Example 1 Toothpaste with biotin antagonist of the biotin inactivator type.

Calcium pyrophosphate 40% glycerin 20% sorbitol 10% sodium lauryl sulfate 1.5% carboxymethyl cellulose 1.0% methyl p-hydroxybenzoate 0.2% saccharin 0.12% propyl p-hydroxybenzoate 0.05% avidin 0.00056% flavoring agent according to taste

Water q. s. to 100 Avidin is adsorbed on the bentonite. This adsorption represents a first stage in a published method of isolation of avidin from egg white (11. Fraenkel-Conrat et al, Arch. Biochem. 39 (1952) 80), It is expedient and desirable to add the avidin to the agents according to the invention in Add the form of the avidin-bentonite adsorbate. In the cited reference the ratio of avidin to bentonite in the adsorbate is 1: 250.

Example 2 Toothpaste with avidin-bentonite adsorbate as biotin antagonist of biotin inactivator type.

Calcium pyrophosphate 40% glycerin 20% sorbitol 10 sodium lauryl sulfate 1.5t carboxymethylcallulose 1.0% avidin-bentonite adsorbate 1: 250 0.1495 methyl-p-hydroxybenzoate 0.2% saccharin 0.12% propyl p-hydroxybenzoate 0.05% flavoring agent to taste Water q.s. to 100 Example 3 Toothpaste with biotin antagonist of the biotin antimetabolite type.

Calcium pyrophosphate 40% glycerin 20% sorbitol 10% sodium lauryl sulfate 1.5% carboxymethyl cellulose 1.0% methyl p-hydroxybenzoate 0.2 9 saccharine 0.12% Propyl p-hydroxybenzoate 0.05% desthiobiotin 0.00056; Flavoring title after Taste water q.s. until 100 Example 4 Toothpaste with Biotin - Antimetabolite and biotin inactivator calcium pyrophosphate 40% glycerin 20% sorbitol 10% sodium lauryl sulfate 1.5% carboxymethyl cellulose 1.0% methyl p-hydroxybenzoate 0.2% saccharin 0.12 % Propyl p-hydroxybenzoate 0.05% avidin 0.00028% desthiobiotin 0.00028% flavoring agent to taste water q.s. up to 100% Example 5 Toothpaste with added tin (II) fluoride and alpha-methylbiotin as a biotin antagonist of the biotin antimetabolite type.

Calcium pyrophosphate 40% glycerin 20% sorbitol 10% sodium lauryl sulfate 1.5 90 carboxymethyl cellulose 1.0% stannous fluoride 0.4% methyl p-hydroxybenzoate 0.2% saccharine 0.12% propyl p-hydroxybenzoate 0.05% alpha-methyl biotin 0.00056% Flavoring agent to taste water q.s. up to 100% Example 6 tooth powder with 1: 250 avidin-bentonite adsorbate as an iotin antagonist of the biotin inactivator type Calcium pyrophosphate 52% sorbitol 40% mannitol 2% sodium lauryl sulfate 2% carboxymethyl cellulose 1.43% avidin-bentonite adsorbate 1: 250 0.3% stannous fluoride 0.40% methyl p-hydroxybenzoate 0.20% saccharin 0.12 propyl p-hydroxybenzoate 0.05% Spray dried Flavoring Agent 1.50 The tooth powder formulations above and below are calculated based on the following considerations: When using tooth powder is the amount of "charge" or serving that is put on the bust, something less than the amount of toothpaste normally applied. Estimated each dose should be close to 0.5 g. There is a certain deviation from this Number can occur, according to the invention is ten times the concentration of the biotin antagonist used to ensure effectiveness. As the amount of dentifrice s the Half the amount used in toothpaste is the concentration of the biotin antagonist has been doubled in the recipe for the powder.

Example 7 Tooth powder with biotin antagonist of the biotin antimetabolite type.

Calcium pyrophosphate 52% sorbitol 40j mannitol 2.4789 e sodium auryl sulfate 2% carboxymethyl cellulose 1.439 tin (II) fluoride 0.80% methyl p-hydroxybenzoate 0.20% Saccharin 0.12t propyl-p-hydroxybenzoate 0.05% desthiobiotin 0.0011% spray-dried Flavoring agent 1.50% Example 8 Tooth powder with both biotin antagonists of the type of biotin inactivator as well as of the biotin antimetabolite.

Calcium pyrophosphate 52% sorbitol 40% mannitol 2.4789% sodium lauryl sulfate 2% carboxymethyl cellulose 1.432 tin (II) fluoride 0.80% methyl p-hydroxybenzoate 0.20% Saccharin 0.12% propyl p-hydroxybenzoate 0.05% Avidin 0.0006% desthiobiotin 0.0005% spray-dried flavoring agents 1.50% produced according to the invention Mouthwashes differ in their purpose from most mouthwashes offered today. While the purpose of the latter seems to be that they are the microflora in the Practically eliminating the oral cavity, the benefits are in reality largely more aesthetic Art. The use of mouthwashes produced according to the invention is likely to be one of them from a wide variety of dental care aids can be viewed by the invention will be made possible with maximum benefit from the application of most Aid is pulled.

The active ingredient calculations for the mouthwashes are the same as those for toothpastes and tooth powder in that, at the time of use, it contains the biotin in the Mouth is to be counteracted. This in turn is called the amount in 10 ml of saliva taken, i.e. more than would normally occur, being ten times the dose of the biotin antagonist is used. The amount of mouthwash that is most common is applied at one time, is in the range of 15 to 30 ml. By applying the a smaller number increases the safety of the effectiveness.

The dose is the same as in the case of toothpastes and toothpowders of the biotin antagonist required for use is about 0.56 pg. Round off and take into account the slightly lower density as a result of the alcohol content of the solution, and if you multiply by 10 as the safety factor, you get a Number around 40 biotin antagonist per 100 g of mouthwash.

Example 9 Mouthwash with biotin antagonist from the class of biotin inactivators.

Weight

S.D. Alcohol 38B 12 Glycerin 10 Sodium Lauryl Sulphate 2 Polysorbate 20 1 carboxymethyl cellulose 0.5 methyl p-hydroxybenzoate 0.2 propyl p-hydroxybenzoate 0.05 sodium saccharin 0.02 avidin 0.00004 flavoring agent to taste water q.s. to 100 Example 10 Mouthwash with a biotin antagonist from the class of the biotin antimetabolites.

Wt% S.D. Alcohol 38B 12 Glycerin 10 Sodium Lauryl Sulphate 2 Polysorbate 20 1 carboxymethyl cellulose 0.5 methyl p-hydroxybenzoate 0.2 propylene p-hydroxybenzoate 0.05 sodium saccharin 0.02 desthiobiotin 0.00004 flavoring agent to taste Water q.s. to 100 Example 11 Mouthwash with biotin antagonists from the classes of inactivators and antimetabolites wt.% S.D. Alcohol 38B 12 Clycer in 10 Sodium lauryl sulfate 2 polysorbate 20 1 carboxymethyl cellulose 0.5 methyl p-hydroxybenzoate 0.2 propyl p-hydroxybenzoate 0.05 sodium saccharin 0.02 avidin 0.00002 alpha-dehydrobiotin 0.00002 Flavoring agent to taste water q.s. up to 100 All means, with which biotin antagonists can be brought into the oral cavity are found to be useful viewed as shown in this description. Means high concentrations These ingredients maintain in the mouth are even more desirable. Has chewing gum Properties by means of which it is assigned to the latter class.

Chewing gum has the ability to limit the release time of its ingredients to extend. This is from experience with the release of sweeteners and flavorings known. Even before the actual release, biotin antagonists can be in the The matrix of the chewing gum come into contact with and react with biotin.

Calculations of the optimal concentrations to be incorporated into the chewing gum of biotin antagonists must take into account a factor that has not been emphasized so far been st, and (read is: the element of time.

Biotin is brought into the mouth with saliva. The salivation is up continuous and, as already mentioned, became at a maximum flow of 288 ml / hour

measured under stimulation conditions. These would be the conditions in the mouth while the gum is being chewed. According to the invention a figure of 300 ml / hour is used for the calculations. applied and the calculations based on a chewing time of 1 hour per piece of chewing gum. After that time is the taste of the chewing gum has just disappeared and the chewing gum is free to throw away. With a biotin content in the saliva of 0.8 pg / 1, they have formed in one hour 300 ml of 0.24 pg nicotine brought with it. At a ratio of biotin antagonist to biotin of 70: 1, this requires 16.8 pg of the antagonist. While at the beginning of the in question coming time the biotin antagonist in substantial excess the situation towards the end of the lesson is inevitably uncertain. For this reason, according to the invention, it is preferably essentially double calculated concentration incorporated by using 30 µg per stick of chewing gum will.

There are some aspects of the situation that are considered natural after the gum has been chewed for some time. Once the sugar is in Rubber pulled out and swallowed. rerner lowers the constant flushing effect, which takes place from this point onwards, inevitably the concentrations of the food residues, which usually provide nutrition for bacteria. The combination of reduced Availability of biotin and reduced diet can only be beneficial for the individual Be a user.

A precautionary rule must be observed when manufacturing the product, if avidin is the biotin antagonist used, and this affects temperatures, to which the latter is exposed. Avidin is a little less sensitive to Denaturation by heat as protein itself, however, there should be no temperatures exposed to temperatures above 900C and should only be added to the rubber when the melt has been cooled to below 600C. When using avidin as a means this can advantageously take the form of the avidin-bentonite adsorbate already described as bentonite is often used in chewing gum.

Example 12 Chewing gum with biotin antagonist of the biotin activator type.

Chewing gum, 1 stick 3 g avidin 30 Example 13 Chewing Gum with biotin antagonist of the biotin antimetabolite type.

Chewing gum, 1 stick 3 g desthiobiotin 30 Example 14 chewing gum with biotin antagonists both of the biotin inactivator and of the biotin antimetabolite type.

Chewing gum, 1 stick 3 g avidin 15 alpl1a-methyldesthiobiotin 15 confectionery or sugar confectionery, especially those like hard candies, that take some time to dissolve Requiring in the mouth are another form of vehicle for introducing biotin antagonists in the mouth in order to carry out dental care of the type according to the invention.

Using a candy the size of the "Life Savers" as a model each piece was found to weigh about 2.5 grams to take about 10 to 12 minutes to dissolve needed in the mouth. Since this is a time when the greater amount of biotin with the Saliva is released, this is the value on which the following calculations are based lies. 12 minutes is 1/5 of an hour, and with a maximum saliva flow below Stimulation of 100 ml of saliva will release 60 ml of saliva during this time. At 0.8 mg biotin per liter, the 60 ml saliva releases 0.048 pq biotin; this can be rounded down to 0.05 µg.

This 0.05 pg biotin would be 3.5 µg biotin antagonist according to the principle of the invention require the possible consumption of the vitamin by the microflora turn off. According to the invention, it is preferable that double the amount becomes larger Security of Effectiveness incorporated. This would be 7 1q i3iotin-Antaqonist per 2.5 / piece of hard candy, the absorption of which requires 12 minutes. The percentage Quantity equals 280 Since there are so many different types of confectionery and confectionery, it is when performing the calculation of the biotin antagonist to be added It is advantageous to use the time factor normally required to accommodate the Piece of the confectionery in question is required. In the above Paragraph stated that a dissolution time of 12 minutes of a Biotin Antaqonist dose of'7, ug corresponds. This gives 0.58 pg biotin angatonist per minute of time up to the dissolution or inclusion of a certain type of confectionery. The term "recording" is likely to be more appropriate, especially in the case of confectionery, more chewable Shape.

As mentioned in the previous section on chewing gum, are in cases where there is a possibility that the used as a biotin inactivator Avidin is exposed to elevated temperatures, precautions to be taken to prevent the avidin from being added at temperatures approaching 90 ° C will.

The addition should expediently be delayed until the confectionery melts has cooled down to at least -600C to be on the safe side.

Due to the fact that the biotin antagonists can be taken in confectionery are, according to the invention, the representatives of the two classes of biotin antagonists limited to just two: avidin for the biotin inactivator type and desthiobotin for the type of biotin antimetabolite. Avidin as a natural component of eggs has been absorbed by humans for many centuries. As already mentioned, it has been shown for desthiobiotin that it is a precursor for biological gische Synthesis of biotin is able to be effective.

To include other types of confectionery, examples have been given Tests carried out to find the average consumption times of caramel candies with a weight of 9 q each and with stick-shaped permanent lollipops of the "3 musketeers" type with a weight of 58 g each. The consumption time was the former an average of 90 seconds each, while the latter is a long one Range from 3 to about 4 minutes, so that the number of 4 minutes is used as a basis will.

The caramel drops then require 0.87 pg biotin antagonist per 9 q, and the permanent lollipops require 2.32 eq / stick of 58 g each.

Example 15 "Life Saver" type confectionery with avidin as biotin antagonist of the type of biotin inactivator.

Hard candy base 100 g Avidin 280 jig Example 16 Confectionery from Caramel type with desthiobiotin as a biotin antagonist of the biotin antimetabolite type.

Caramel base 100 g desthiobiotin 10 pig Example 17 permanent lollipop of the "3 musketeers" type with biotin antagonists and of the biotin inactivator type as well as of the biotin antimetabolite type.

Candy base 100 g Desthiobiotin 2 µg Avidin 2 µg A note about The addition of avidin to confectionery is appropriate at this point: Da confectionery edible, it is entirely possible to add avidin if desired is, add by adding appropriate amounts of protein. For the purpose of Calculating the amount of protein to be added one only needs to think about that protein on a dry basis contains about 0.059s avidin.

On the safety of the use of biotin antagonists described here will be discussed in a later section. The applicant is convinced that this will show that there is no risk of adequate supply of the Body is disturbed by biotin in normal ways. Especially in cases where you double want to ensure that by consuming confectionery that is unusual Contain large quantities of biotin antaonists that do not reduce the biotin supply becomes, it is possible to manufacture confectionery in which biotin in an amount that corresponds to that which is made inaccessible by the antagonist, an external one Layer of confectionery is fed.

Hard candies are best for this type of build-up. After this the body or core of the confectionery containing the biotin antagonist is made the coating containing biotin is added. This can be done by double tabletting or the coating can be applied in a coating pan.

When calculating the concentrations to be incorporated into the confectionery the first step is to determine the dissolution time of the core of a piece of confectionery Dosage of the biotin antagonist using the factor 0.56 pg / min. Dissolution time calculated and the dose of biotin to be included in each coating of each piece, offset with 1/70 of the amount of the biotin antagonist.

The variety of confectionery types that have been thought of is almost innumerable. In the illustration above is a guy who not intended for chewing, has been treated. »E application of the invention can be expanded in many ways intended for chewing by the consumer is instructed to hold the confectionery in the mouth for a short time until the Biotin-containing coating is dissolved. An expedient measure to this Point to indicate would be the use of a flavor in the coating different from that of the The core of the confectionery is different. When the consumer changes in taste perceives, he knows that the coating has dissolved and absorbed the biotin has been.

The piece could then be chewed with the certainty that that the advantages of the invention have been realized.

Example 18 "Life Saver" type ifart candy containing biotin Coating and biotin antagonist of the biotin inactivator type in the core.

Hard candy base 100 q Avidin 280 eg After tablets are formed they are placed in the Draqier cauldron and covered with the following Composition: Sugar 5 g water 5 g Biot in 4 11 g Example 19 hard candy of the "Life Saver" type with a biotin-containing coating and a biotin antagonist of the type of the biotin anti-metabolism in the core.

liartbonbongrundlage 100 g Desthiobiotin 280 mg After the tablets have been formed, they are placed in the coating pan with a solution the following composition is applied: Sugar 5 q water 5 g Biotin 4 ig Example 20 Hard candy of the "Life Saver" type with biotin-containing Coating and biotin antagonists both of the biotin antimetabolite type and of the type of biotin inactivator in the core.

Hard candy base 100 g Desthiobiotin 140 mg Avidin 140 After the tablets have been formed, they are placed in the coating pan to which a solution of the following composition is applied: sugar 5 g water 5 g biotin 4 pg Another means of applying the principle of the invention is represents a tooth coating concentrate, which is described below. It deals is a solution intended to be applied to the teeth between meals and a biotin antagonist in a much higher concentration than a mouthwash contains. It also differs from mouthwash in that it is after Use is not rinsed out. The concentrate is expediently as mild as possible The taste is kept so as not to stimulate the formation of saliva, as this is also biotin would bring to the scene. The concentrate is intended to be used on the tooth surfaces to stay where its biotin antagonist content is most effective the biotin uptake can block by microorganisms that cause tooth decay.

The concentration of the biotin antagonist in the concentrate is the Based on the time taken for the concentrate to remain effective will. The calculations below assume a duration of 1 hour toqrunde. Longer times are burdened by increased uncertainties resulting from effects such as swallowing, speaking, smoking and other activities result can have that the coating is removed from the teeth.

without stimulation, the maximum salivation rate in the already mentioned publication with 110 ml / hour.

specified. The amount of biotin in 110 ml is therefore the maximum that can get through a treatment must be made inaccessible, and at a concentration of 0.8 pg / liter saliva results in 0.088 µg biotin. At the ratio of the biotin antagonist of 70: 1 this requires a dose of 6.16 jig of the latter. 10 µg represent one some excess and a useful factor in calculations.

Using either a rag or a spray is a lot of 0.5 ml is sufficient to form a coating on the teeth. At one dose of 10 jig per 0.5 ml result for the percentage of the biotin antagonist in concentrate 2000 jig or, to put it more simply, 2 mg. To the risk of having a Person takes excessively large amounts of the concentrate, largely switch off, it is convenient to put it in 5 ml ampoule bottles, which are provided with narrowed openings are, similar to the product known as "Binaca", the breath freshener in the Trade is to pack.

One could expect that the tooth surfaces with which the Tongue comes into contact, soon after the application of the concentrate free of it getting washed.

This is not too much of a concern as there are always very few cavities form on these surfaces.

The areas in which rest conditions prevail are historical: in crevices between teeth and at the gum line, in other words, everywhere, where Deposits physically more or less "hidden" and stay undisturbed.

Example 21 Tooth coating concentrate with biotin antagonist of the type of the biotin antimetabolite.

Glycerin 30% carboxymethyl cellulose 2% bentonite 2% methyl p-hydroxybenzoate 0.2% propyl p-hydroxybenzoate 0.05% desthiobiotin 0.002 flavoring agent Taste water q.s. to 100 The aforementioned. Avidin bentonite adsorbate can can be used advantageously for this purpose. It saves the additional measure the separation of avidin during its purification.

Example 22 Tooth Enveloping Concentrate With Biotin Antagonist Type of the biotin inactivator.

Glycerin 30% carboxymethyl cellulose 296 avidin-nentonite adsorbate 1: 250 0.5.

Bentonite 1.5 3 methyl p-hydroxybenzoate 0.2 9i propyl p-hydroxybenzoate 0.05 flavoring agent to taste water q.s. to 100 It is for the expert it is apparent that other ingredients such as surfactants, viscosity regulators and additives that improve the appearance, in the context of the invention, the concentrate can be added. The concentrations of the biotin antagonists can also can be changed so that an effect is achieved for different periods of time or the Service life is changed. Other biotin antagonists or their mixtures can also be used be incorporated.

The following example gives a recipe in which a mixture of Biotin antagonists is used.

Example 23 Tooth Covering Concentrate With Both Biotin Antagonists from the class of biotin antimetabolites as well as from the class of biotin inactivators.

Glycerin 30% carboxymethyl cellulose 2% bentonite 2% methyl p-hydroxybenzoate 0.2% propyl p-hydroxybenzoate 0.05% desthiobiotin 0.001% avidin 0.001% water q.s. to 100 1 'in or more means by which the microflora of the mouth supply them With biotin withdrawn, oral tablets represent the biotin antagonists contain, and release the active ingredient over a longer period of time.

When tablets of this type are put in the mouth, it is steady Supply of one or more substances that make the biotin ineffective, via a longer period possible. Its use is particularly recommended for times in which one rests, and the example described in detail relates to one 8-hour tablet, as this time largely qilts as normal night sleep.

The calculations were made on the following bases: Saliva formation without stimulation: maximum 110 ml / hour.

Biotin content of saliva: 0.8 pg / liter ratio of effective Biotin antagonists to biotin: 70: 1 Desired duration of effectiveness: 8 hours There are two basic types of extended-release tablets of one type, there is a substantially insoluble matrix of which an active ingredient is present is leached out over a period of time. The other type will dissolve the entire tablet slow on, the excipient and the active ingredient released together will. According to the invention, the latter type is preferred. The manufacture of this The type of tablet is described in U.S. Patents 3,039,933 and 3,362,881.

Both types of tablets have one property in common: while they clearly show that they allow an extended release time for the active substance no constant release rates. At the tablet of the stable matrix type, diluted The reservoir of the active ingredient gradually increases more and more. With the guy who dissolves the tablet becomes smaller over time and the surface area becomes smaller also the dissolution speed is lower. Either way, this leads to one gradual decrease in the rate of release of the active ingredient. In some In cases, this retention is the same as with medicaments in which a certain concentration of the active ingredient is to be adjusted., desired, and then only much lower lying Maintenance concentrations desirable. This situation is within the scope of the invention undesirable and requires countermeasures.

To clarify the process that took place during the dissolution of Tablets of this type takes place, consider an 8-hour release tablet, which is supposed to counteract the biotin brought into the mouth with the saliva.

At 110 ml / hour and 0.8 pg / liter of biotin would be the maximum released Bring 880 ml 0.704 1lg biotin with it. From the above mentioned fact 1:70 for the value of the biotin antagonist results in 49.3 µg for the release over a period of 8 hours

should be incorporated. However, this amount remains constant As the rate is released, the average rate would only be in the middle this time d double the rate in the first half of the period and the half the rate in the second half of the period.

At first glance, one should assume that one is coping this situation should double the dosage in the tablet, however this is only part of the answer to the solution: the tablet is accurate towards the end of the period so consumed, and the rate of release is nearing the end of the Period too low if the active ingredient has not been added in large excesses is.

This problem is solved according to the invention by using a tablet of 16 hours in duration, with a double dose of the biotin antagonist is started. In this way the mean release rate of the tablet is after 8 hours just reached. The release rates before this point in time are higher than they are actually needed, however there is a protection to all Times secured.

The tablet would then contain 98.6 µg of biotin antagonist and for a duration of 16 hours, but only 8 hours are needed. Indeed the dosage is best divided into 2 tablets, one of which is at bedtime one placed near each cheek.

It should be noted that tablets of this type according to the invention with prolonged release of the active ingredient also for other periods, e.g. for the Use between meals, can be made.

The calculation for the dosage is twice the amount that is required is to the amount of biotin that is released in the time that one wishes to capture can be counteracted, and the tablet should be in twice the duration this time be resolvable.

It should be noted that a limitation of the invention to the tablet form, which is used as a carrier for the biotin antagonist is not intended. Appropriate the tablet base belongs to the class of substances such as carboxymethyl cellulose, Polyacrylic acid and similar substances that are not readily susceptible to food for microorganisms deliver. Natural gums are often used as food for bacteria and molds and are less beneficial. Likewise, the invention is limited to that described special tablet with 16 hour release of the active ingredient is not intended. With a multi-layer tablet with a very high internal concentration of the biotin antagonist and successively lower concentrations in the outer layers a release rate that is more constant can be achieved, but the increased cost A more complicated tablet must be against the cost of using something more biotin antimetabolite to maintain effectiveness in an easier way manufactured tablet are weighed.

Example 24 Extended release oral tablets for Effective for 8 hours with biotin antagonist of the biotin inactivator type.

Basis of the extended release tablets 100 g avidin 4.93 m g tablets of 1 g each are pressed in such a way that a duration of action of 16 Hrs.

2 tablets are placed in the mouth at bedtime, one for each adjacent to each cheek.

Example 25 Oral Extended Release Tablets for 4 hours of use between meals with biotin antimetabolite-type biotin antagonist.

Basis of tablets with extended release 100 cc I) es Lh iobiotin 2.97 mg tablets of 1 g each are pressed so that they have a duration of action of 8 hours.

2 tablets are placed in the mouth at bedtime, one for each adjacent to each cheek.

Example 26 Oral Extended Release Tablet for Effective for 8 hours with both biotin antagonists and biotin inactivator types as well as of the biotin antimetabolite type.

Base of the tablet with extended clearance (above 100 g avidin 2.97 mg desthiobiotin 2.97 mg tablets of 1 g each are pressed so that they have a duration of 16 hours.

2 tablets are placed in the mouth at bedtime, one for each adjacent to each cheek.

Below are some considerations about potential health hazards from the application of the invention.

Since biotin is an essential vitamin for humans, the possible must Effects on the supply of humans and the reserves created by maximum Application of the features of the invention could be generated.

The following are the main factors that make up the overall picture result: 1. The treatments are only aimed at the biotin that is in the mouth is located. You are not relying on the body's supply of biotin to decrease concentrations in the mouth directed. With the order of magnitude of what is to be rendered ineffective 13lotins and the order of magnitude of the funds used are one ecosystem represented by less than 10 ml of saliva at any point in time, and a total daily production is with a maximum of 1500 ml both by the biochemists' Handbook (Van Nostrand, 1962) and from the Textbook of Biochemistry by West & Todd (MacMillan, 1952) stated. The first mentioned publication names one Biotin content in saliva of 0.8 µg / liter. Even with a maximum of 2 liters Saliva amounts to the total biotin that could be rendered ineffective only 1.6 pg per day.

The antagonists could maximally even with excesses of 100% only 3, 2 pq biotin per day ineffective at all.

2. The human body, which is a much larger system, receives biotin supplies from two sources (Recommended Dietary Allowances, published von NAS, 1974): a) from food: 100 to 300 µg per day b) from normal intestinal flora in amounts so high that they are 3 to 6 times that of the diet Amount that is excreted as excess in the urine. Even the application of these factors on the smaller number of biotin from food yields numbers of 300 to 600 pg the body it needs beyond its needs. If you spill this off Data m di show that 1. the amounts of biotin that may be produced by the application of the Invention ineffective are slightly above 3 ug, with 2. the biotin excesses from 300 to 600 mg, one can rightly say that there is a risk of biotin deficiency could occur is extremely unlikely.

Further facts reinforce the impression of confidence in maintenance adequate biotin supply for the body. Once the NAS no RDA values for biotin due to the abundant intake of this vitamin in ours Food set. In one carried out by Sydenstricker (JAMA 118 (1942) 1199-1200) In the experiment it was found necessary to give test subjects a 30% protein Administer diet 7 weeks before acute symptoms of biotin deficiency are observed became.

The dosage of avidin was massive: it was enough to keep biotin in the Inactivate of the order of 900 p / day.

The ability to withdraw less than 4 pg biotin per day from the body, makes it unlikely that similar effects will be obtained by applying the invention can be evoked.

Claims (2)

Z a h n p f 1 e g e m i t t e 1 P a t e n t a n s p r ü c h e 1. Dentifrices made from dentifrices including toothpastes and toothpowders, Mouthwashes, chewing gum, confectionery and confectionery including those with a biotin containing outer layer, tooth coating concentrates and oral tablets with extended Active ingredient release existing group, characterized in that they are biotin antagonists contain in effective amounts1 the optimal microorganisms needed for biotin, which in the mini ecosystem of the human mouth the formation of tartar, tooth decay and Acids have the effect of creating unfavorable conditions that block the uptake of biotin. 2. Dental care product according to claim 1, characterized in that it Biotin antagonists of the biotin inactivator and / or biotin antimetabolite type contain.