Health Care

Dental health-care aids

Health Care Abstract
Dental-care Aid Products are formulated to contain Biotin-antagonists. Biotin is an essential nutrient for many microorganisms involved in tooth decay; restricting Biotin availability for the microflora by means of Biotin-antagonists interferes with their ability to develop dental caries.

Health Care Claims
I claim:

1. Dental Health-care Aids compositions selected from the group consisting of dentifrice toothpastes dentifrice toothpowders mouthwashes chewing gums confections tooth-coating concentrates and extended-release buccal tablets comprising effective amounts optimum for a biotin-uptake blocking regimen unfavorable for biotin-requiring micro-organisms implicated in the human mouth mini-ecosystem production of dental caries plaque, and acid formation, in the mouth of Biotin-antagonists. Patent Information Search Body

Health Care Description
BACKGROUND OF THE INVENTION

1. Field of the Invention

This application relates to Dental-care Aid Products; these incorporate Biotin-antagonists for the purpose of inhibiting the development and effects of caries-producing microorganisms in the human mouth.

2. Description of the Prior Art

No previously used or described products are known to the inventor, of any kind, whose function it is to control the environment in which oral bacteria exist, in such a way as to deprive them of the full use of necessary Vitamins that are normally present in the saliva.

SUMMARY OF THE INVENTION

This invention is based upon the principle of severely limiting the availability of Biotin, which is normally present in human saliva, to those microorganisms in the human mouth, that are the prime causative agents of tooth decay. It has been found that Biotin is an essential nutrient for these microorganisms, and the Biotin-deprivation is intended to severely limit their development, and consequently their ability to create caries. The Biotin-deprivation is brought about by the introduction through various Dentalcare Aid products, of Biotin-antagonists into the human mouth. It is an important and noteworthy feature of the invention that the Biotin-antagonists bring about their effects directly in the miniecosystem that exists in the human mouth; Biotin stores in the body proper are not intended to be affected and in the magnitudes of Biotin-antagonists involved, the possible effects on total body stores of Biotin are insignificant.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purpose of elucidating this invention, some background is first provided on the mechanism of tooth-decay, on the vitamin Biotin, and the requirement of decay-fostering microorganisms for this vitamin, and on Biotin-antagonists that are able to block the normal pathways of Biotin-uptake by the offending microorganisms.

The mechanism whereby dental caries appear to be formed is based on a two-fold effect: first, the accumulation of plaque on the tooth surfaces by the action of one type of microorganisms that produce carbohydrate-based polymers such as dextrans. Secondly, there is the production of acids, usually by another group of microorganisms, and these are the cause of the actual breakdown in the integrity of the tooth structure.

The acid-formers inhabit the plaque; in addition to providing a sheltered environment for these bacteria, the plaque can also provide them with nutrients. Also, the plaque can hold the acids that are produced in close proximity to the tooth-surfaces, so that the acids are less likely to become diluted, or even washed away from the tooth surfaces by other liquids in the mouth.

Plaque is based mainly on sucrose polymers, and the microorganism most strongly suspected of being responsible for its formation is Streptococcus mutans. This was reported by J. K. Clark in 1924 (Brit. Jour. Exp. Path. 5:141-147). The monumental work on this subject has been done more recently by J. Carlsson (Odont Revy 18: 55-74 (1967), Ibid 19:137-160 (1968), Ibid 19: Suppl. 14 (1968)). In 1970 Carlsson sought to establish nutrient needs for Streptococcus mutans. Using a strain designated as JC2, which was isolated from humans, he found Biotin to be essential for growth (Caries Research 4:305-320 (1970)).

The acid-producing microorganisms have similar requirements: In 1944 Niven (Jour. Bact. 47:343-350) showed that of 21 strains of Streptococcus lactis examined for vitamin requirements, all needed Biotin for growth. In 1950 S. A. Koser and H. J. Fisher isolated 26 strains of Lactobacilli from human saliva and found that Biotin was essential for growth for all of them (J. Dental Res. 29:760-773).

While Lactic Acid seems to be considered to be the acid most responsible for tooth decay (A. T. Brown in Present Knowledge of Nutrition, 1976, by the Nutrition Foundation, p. 492) "particiating in the deminerilization of enamel and cementum in coronal and root surface caries", one cannot wholly exclude the possible contribution of other acids, such as Propionic, to this effect. In this regard E. A. Delwicke (J. Bact. 1949, 58:395-398) reported that of 25 strains of Propionibacterium, most required Biotin for growth.

Biotin is a vitamin that is involved in the respiratory function of organisms, and appears to be required by almost all forms of life. Some organisms are able to synthesize their own, others obtain it from outside sources. It is a fortuitous circumstance that many of the microorganisms implicated in the production of dental caries require an outside source of Biotin. This creates a situation in which Biotin-depletion can be used as a tool for the inhibition of their development, and this is precisely what this invention does. By following a regimen that persistently blocks Biotin uptake, conditions can be made unfavorable for both plaque and acid formation, with resultant benefits in dental health.

Biotin-depletion or Biotin-deprivation for the caries-producing microorganisms in the mouth is brought about by the use of Dental-health Aid Products that introduce Biotin-antagonists into the mouth. There are two classes of Biotin-antagonists. The first and more numerous are the ones called "Biotin Antimetabolites".

D. W. Woolley in his book "A Study of Antimetabolites", Wiley, 1952, defines Antimetabolites as "structrual analogs antagonistic to metabolites". The structural similarity to the active Metabolites is postulated to be responsible for attachment of the Antimetabolite to sites normally receptive to the true Metabolite; this blocks the sites, and at least temporarily prevents the true Metabolite from coupling with the substrate. Coupling action with either the Metabolite or Antimetabolite is considered to be a reversible reaction, and the sites are considered to become available and then occupied over and over again. The question of which agent is most likely to attach to an available site is strictly a matter of the ratio of concentrations of Metabolites and Antimetabolites in the environment; with equal concentrations of both, equal numbers of sites are occupied by each. In order to get only 1% of the sites occupied by an active metabolite, there must be a 99 to one ratio of Antimetabolite to Metabolite concentrations.

The literature lists a substantial number of compounds that are Biotin-antimetabolites. Not all modifications of the Biotin molecule result in antagonistic properties; the compound known as Oxybiotin, for instance, in which Oxygen is substituted for the Sulfur in the molecule still retains vitamin activity in some instances.

In order to be able to visualize the modifications that are made to create Antimetabolites, the structure of the original active Biotin is shown: ##STR1##

Empty valence bonds are understood to be attached to Hydrogen.

Examples of Biotin Antimetabolites are:

Desthiobiotin with 2 H substituted for S.

Biotin Sulfone with SO.sub.2 substituted for S.

Ureylene Cyclohexyl Aliphatic Acids with 2 C substituted for S and derivatives with shorter side chains.

Desthio Iso Biotin substituting 2 H for S and having geometric isomerism.

Ureylene Tetrahydro Furyl Aliphatic Sulfonic Acids with O substituted for S and SO.sub.3 H for COOH.

Homobiotin with addition of --CH.sub.2 -- in the side chain.

Ureylene Cyclohexyl Valeric Acid substituting a six carbon ring for the four carbon and one sulfur 5 membered ring.

Alpha Dehydro Biotin with a double bond alpha to the COOH.

Alpha Methyl Biotin with a Methyl group on the Carbion alpha to the COOH.

Alpha Methyl Desthiobiotin with a Methyl group alpha to the COOH and 2 H in place of S.

Six Carbon-sidechain Oxybiotin with an additional C in the side-chain and substituting O for S.

Oxybiotin Sulfonic Acid substituting O for S and SO.sub.3 H for COOH.

The literature also lists:

nor Biotin

bis Homobiotin

tris Homobiotin

4 Imidazole Aliphatic Acids

2 Oxo-4 Imidazolidin Caproic Acid

Thiazolidone

Benzyl Thioethers

Hydrazides and Semicarbazides of Biotin

bis Hydrazides of Suberic and Sebacic Acids

Methyl 1-3-acetyl-4-thiazolidine Carboxylate

1-2-propyl-3-acetyl-4-thiazolidine 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 Antimetabolite for use in this invention is not as difficult as the great number of possible Antimetabolites might imply. Compounds such as the Antibiotic Thiazolidone bring with them risks of the development of antibiotic-resistant strains of bacteria, and are to be avoided. Compounds that are very different from those encountered in living organisms can be eliminated, especially in view of the fact that ones very similar are available. Those with such minor changes as the addition of a Carbon in the side chain or unsaturation brought about by elimination of H from the side chain would be promising as candidates having low toxicity, but the most logical of all is Desthiobiotin, since it has been quite definitely established to be the Biotin precursor in some microorganisms, notably E. coli.

A very strong possibility exists that any amounts of Desthiobiotin that may be ingested by humans can be used by the intestinal microflora to manufacture Biotin, which in turn can be taken up by the human body. It has been shown that much of the Biotin supply to the body is provided by its normal intestinal microflora.

The second class of Biotin Antagonists is that of the Biotin Inactivators that combine with Biotin in such a way as to render it incapable of functioning as a vitamin.

Examples of the class of Biotin Inactivators are:

Avidin, present in the whites of eggs from avians and amphibians.

Streptavidin, produced by Streptomyces species.

An Avidin-like compound found in egg yolk. (H. W. Meslar et al, J. Biol. Chem. v 253, n 19, pp 6979-6982 (1978)), also J. C. McGuire et al, Biochem. J. 157 (2): 395-400, Aug. 1, 1976).

A Biotin-binding Protein found in chicken plasma (R. D. Mandella et al, Biochem J. 175(2) 1978 p629-634.)

Avidin is the most plentiful of the compounds of its class and having been known for the longest time, is also the best known. It is a complex Glycoprotein, having a molecular weight of 68,000. It occurs in the egg-white of chickens to the extent of 0.05%. Each molecule of Avidin has four active sites at which it can bind to Biotin. The combination formed between Avidin and Biotin is very strongly bound; the dissociation constant is 10.sup.-15 (N. M. Green, Nature, 217 (1968) p.254). The combination effectively renders Biotin incapable of acting as a vitamin.

For the purposes of this invention, one member of the class of Biotin-inactivating Biotin Antagonists of choice is Avidin.

In deciding which class of Biotin Antagonist to use for the purpose of depleting the Biotin supply available to oral microflora it is important to examine the different effects provided by each. On the one hand, a Biotin-inactivator such as Avidin, when present in sufficient amounts to react with all of the Biotin available, will completely render the Biotin unavailable to the microflora. Because of the fact that Avidin has a molecular weight of 68,000 and Biotin has a molecular weight of 244.3, and one mole of Avidin reacts with four of Biotin, the stoichometric ratio of reactants is 68,000 to 4.times.244.3 or 69.6 to 1. This rounds off to 70 parts by weight of Avidin to one part by weight of Biotin. So as long as there is at least 70 times as much Avidin as Biotin, the latter will be inactivated.

With a Biotin Antimetabolite in the ratio of 70 parts to one of Biotin, Biotin activity will be reduced to 1/70th of its normal value, which is unquestionably an appreciable reduction, while not a complete reduction to practically zero.

When Biotin Antagonist concentration falls off, for instance between applications, while Biotin continues to be supplied by saliva, the relative effectiveness of the Biotin Antagonist that still remains, changes, depending on its type. With Avidin, for instance, a reduction to half, that is, 35 parts of Avidin per part of Biotin, can only inactivate one half of the Biotin. A reduction of Antimetabolite from 70 parts to 35 parts per part of Biotin brings about a change from Biotin activity of 1/70th to one of 1/35th of its activity. The Biotin Antimetabolite therefore has advantages when the more ideal ratios begin to fall off.

In the examples that follow, calculations of the amounts of Biotin-antagonists to be incorporated are based on data given in the Biochemists' Handbook, Cyril Long, Editor, published by Van Nostrand in 1961. The reference shows these significant data:

Mean Flow Rate of "Resting" Saliva: 30 ml/Hr. Range: 2.5 to 110 ml/Hr.

Mean Flow Rate of Saliva Under Stimulation: 114 ml/Hr. Range: 24 to 288 ml/Hr.

Biotin Content of Saliva: about 0.8 micrograms per liter.

In order to insure effectiveness in all applications, the calculations for Biotin Antagonist concentrations that follow are all based on maxima of saliva flow rates, and consequent maximum rates of Biotin-release into the mouth. It is the ever-replenishing supply of Biotin into the oral cavity by the saliva that must be countered by the type of treatment envisioned in this invention, and in order to really be effective there should be an unflagging persistance in applied effort to block the microflora's access to the necessary Biotin. In order to make this more possible, the invention provides a variety of means for introducing Biotin- antagonists into the oral cavity. These means are

Dentifrices

Mouthwashes

Chewing Gum

Confections

Tooth-coating Concentrates

Extended-release Buccal Tablets.

in order to illustrate these various means, the following examples of formulas are given.

Dentifrices

Dentifrices made according to this invention may be formulated either as tooth-pastes or tooth-powders.

Tooth-pastes have the customary ingredients such as water, abrasives, humectants, surfactants, flavorings, and may also include compounds that contribute fluoride ions or stannous ions and other items that suggest themselves to those skilled in the art, but most particularly and specifically, they comprise Biotinantagonists. Also, since such possible components as Avidin may be subject to microbial attack, it is desirable to include a preservative, or a combination of preservatives, such as Methyl and Propyl Parahydroxy Benzoates.

The rationale for Biotin-antagonist concentrations used is the following: The amount of saliva in the mouth, in the absence of stimulation, is rather surprisingly small: less than 10 ml, and more often about 4 to 6 ml. With a Biotin content of 0.8 micrograms per liter of saliva, it would mean at the most there would be 0.008 micrograms of Biotin to counteract by the toothbrushing operation. With a 70 to 1 ratio of Biotin-antagonist as a use ratio, this would call for 0.56 micrograms of Biotin-antagonist per operation. A "ribbon" of tooth-paste, as usually applied to the brush, weighs in the vicinity of one to one and a half grams. To be on the safe side, I assume that the smaller amount will be used, that is, one gram. In other words, each gram of tooth-paste should provide 0.56 micrograms of Biotin-antagonist or 56 micrograms per 100 grams.

Since the exposure to the Biotin-antagonist during toothbrushing is of such short duration, and the surfaces to be treated not all readily accessible. I prefer to provide a ten-fold excess of Biotin-antagonist concentration for assured effectiveness, that is: 560 micrograms per 100 grams of tooth-paste.