JPH0737372B2 - Composition for treating dental tissue - Google Patents

Description

Description: BACKGROUND OF THE INVENTION The normal normal flora of the oral cavity is Streptococci and Actinomyces.
myces); rather than a considerable variety of aerobic, facultative anaerobic and obligate anaerobic microorganisms, represented by Neisseria and Norardia; Veillonella and Fusobacterium, respectively. Become. The former is found almost exclusively in the oral mucosa, and the latter two groups are found mainly in the subgingival (below the gum line) site. For example,
Streptococcus forms a colony on the tooth surface and secondary plaque formation; this plaque acts as a matrix both physically and biologically.

It is well known that mammalian teeth are susceptible to cariesogenic manifestations of bacterial exudates, ie, cavities. Caries is essentially the result of the collapse of the tooth material starting from the outer surface and progressing inward. Initially, the tooth surface enamel, which is totally non-cytoplasmic, is demineralized. Basically, this is due to the action of acid products of bacterial fermentation and / or saliva. Following demineralization of the surface enamel, elephant and cementum are generally degraded by bacterial digestion of the protein matrix.

The basic first step in caries development is believed to be due to the formation of plaque on the hard, smooth enamel surface of the dentition. There are quinonoid structures firmly attached in the form of plaque, both gingivally and subgingivally, to the surface of mammalian dentition. Such plaque is highly resistant to chemical attack and can generally only be removed by abrasive means and can serve as a nutrient source for fine teeth. The basic second step in caries development appears to be the production of large amounts of acid from bacteria and / or saliva. Unfortunately, the high concentration of acid demineralizes the adjacent enamel, initiating caries formation.

Plaque is also called "bacterial plaque," and in fact many types of bacteria can be isolated from plaque deposits by conventional culturing techniques. It is generally believed that dental plaque consists of a polymeric form of saliva, the origin of which is salic acid. (They act as monomers that can be easily polymerized in acidic environments). In the basic pH range, in salt form, they are relatively soluble and confer thixotropic properties on saliva. Mucus-like substances often contain substances that give a slimy feel and similar substances. For example, acids generated by bacterial activity on carbohydrates tend to acidify the oral cavity to unusually low pH ranges. This tends to cause polymerization of the neuraminic acid derivative, creating a chemical bond between the normal hydroxyapatite structure of the tooth and the polymerized neuraminic acid. Thus, in juxtaposition with normal biological tissue, the presence of suitable enzymatic substrates may lead to the desired secondary enzymatic conversion of the tissue.

It is well known to regularly remove plaque from the enamel of teeth to reduce the incidence of caries. Furthermore, it is also well known to use a formulation containing available fluoride anions to prevent caries on the surface of teeth by means of which the fluoride ion replaces a hydroxy group or a hydroxy group in the hydroxyapatite structure. It is believed that this is due to the introduction of the theoretical structure fluforapatite or fluorohydroxyapatite through the combination with the group. Such structures appear to be largely insensitive to the cariogenic activity of bacterial exudates, consisting of toxins and similar substances with enzymatic activity, among others. Thus, when such enzymatic activity readily cleaves hydroxyapatite and its attendant phosphate groups, the introduction of the fluorinated fluoride renders the structure almost insensitive to enzymatic degradation. Be regarded. Therefore, since the planned introduction of fluoride into water and the use of dentifrices containing fluoride anions, the incidence of caries decreased significantly, as reported arbitrarily. Has been done.

Therefore, as a means to effectively reduce the occurrence of caries resulting from the activity from normal physiological parasitic bacteria present in the oral cavity, there are two basic methods currently used simultaneously. To do. The first, and less commonly used method is the physical method, which mechanically removes plaque from the tooth surface because it is relatively resistant to chemical attack. It is a method that includes doing. Second
A more commonly used method is a chemical method that is often or daily carried out, for example, by using a dentifrice containing a fluoride to change the normal hydroxyapatite structure of the tooth to fluoroapatite or fluorohydroxyapatite. It is a method related to chemically changing or mineralizing. Basically, the incorporation of fluoride in the tooth tissue renders the tooth resistant to enzymatic degradation, thereby reducing the occurrence of caries.

In addition to the use of fluorides to help prevent the caries formation process, some dental implants have traditionally used divalent metals such as copper, chromium, cobalt and aene as alternative dietary strengthening measures. The formulation is prepared. Examples of such dental formulations are U.S. Pat.No. 4,375,460, U.S. Pat.
4,339,429, U.S. Pat.No. 4,332,791, U.S. Pat.
5,633, U.S. Pat.No. 4,048,300 and U.S. Pat.No. 2,15
It can be found in issue 4,168. Unfortunately, the divalent metal complex compounds described in the above-referenced U.S. patents and incorporated into the dental formulations have hitherto not been generally satisfactory. For example, almost all of these currently used divalent metal complex compounds are relatively insoluble in aqueous media. In addition to this insolubility drawback, these divalent metal complex compounds are very stable in the pH range commonly encountered in the oral cavity, dissociating only trace amounts of metal ions, which is Makes the compound relatively ineffective. Furthermore, due to stability factors, relatively large amounts of divalent metal complex compounds must generally be incorporated into these dental preparations, which has a detrimental effect on the overall taste and mouth feel of the final product. .

For subgingival tissue, this situation is somewhat different,
The soft tissues that face the apatite component are mainly attacked by anaerobic physiological parasitic bacteria. The teeth are attached to the periodontal ligament, as opposed to the jaw's body structure, which is not different from the ligament structure with normal musculoskeletal connections. These periodontal ligaments appear to be extremely sensitive to enzymes secreted by the anaerobic species of bacteria found under the gingiva. The gradual collapse of both ligaments and anatomy eventually leads to the loss of tooth connectivity to bone. This unfortunately causes conduit infections, gingival and peri-crown abscess formation and eventual tooth loss.

Accordingly, attempts have been made in the past to prepare suitable dental compositions for mineralizing teeth to prevent or reduce dental caries. However, no satisfactory dental composition has been developed that can solve the above problems other than those containing a fluoride anion. Basically, known types of divalent metal complex compounds fall into two categories: compounds in which the cations are usually very tightly bound to their relative ions; and cations as hydrous oxides of metals. A compound found in an insoluble form.

In other words, all dental compositions using divalent metal complex compounds other than conventionally provided fluorides are key basics required to provide a sufficient amount of therapeutic metal ions in the oral cavity. Is necessarily lacking in some of the physical properties. Accordingly, there is a strong dentist and market demand for metal complex compound-containing dental compositions suitable for mineralizing tooth tissue in order to reduce or prevent deterioration of the tooth tissue.

Briefly, the present invention provides novel dental compositions and methods of use thereof for treating dental tissues such as teeth and subgingival tissues to reduce or prevent dental caries and its destruction. It is intended to alleviate the aforementioned problems and drawbacks of the state of the art by providing them. It has now been found that a particular group of metal complex compounds is particularly suitable for making available metal ions, such as copper, for preventing or reducing the degenerative progression of tooth tissue. Broadly, the invention includes applying to the oral cavity an effective amount of a 1: 1 metal complex compound of a polyvalent heavy metal ion bound to a polyfunctional organic ligand. As one suitable method for applying the metal complex compound, these compounds can be dispersed in an appropriate aqueous vehicle to prepare a desired dental composition. The 1: 1 metal complex compound according to the present invention has an aqueous proton-induced dissociation physical property shown by an S-shaped curve when the negative logarithm of the metal ion concentration versus the negative logarithm of the hydrogen ion concentration is plotted in Cartesian coordinates. The 1: 1 metal complex compound having such dissociative properties provides it with a unique means for imparting copper ions to tooth tissue for the treatment of disorders.

The polyvalent heavy metal ion can include, for example, bismuth, chromium, cobalt, copper, aene, etc., preferably copper. On the other hand, polyfunctional organic ligands are, for example, alpha or beta hydroxypolycarboxylic acids such as citric acid,
And alpha or beta amino, sulfhydro,
It can be derived from functionally substituted acids such as phosphinol and others. In particular, disodium-, dipotassium- or dilithium-monocopper (II) citrate is particularly suitable for preparing the dental composition according to the invention. In addition, suitable buffering agents may be included in the dental composition, including citric acid, for example, to adjust the pH.

Accordingly, the novel and improved dental compositions and treatment methods according to the present invention for treating dental tissue provide a novel means for preventing caries and subgingival tissue destruction. Surprisingly used in the dental composition of the present invention
The 1: 1 metal complex compound has the property of forming a metal coordination complex compound or salt in the tooth tissue, and making the metal ion readily available for imparting a mineral thereto. The formation of such complex compounds or salts in tooth tissue is particularly effective and extremely resistant to the enzymatic destruction associated with microbial activity in the oral cavity. In addition, this metal ion is extremely effective in inactivating the enzyme secreted by the microorganisms present in the oral cavity, which means that the progress of the destruction of tooth tissue by such enzyme is reduced. .

In another aspect of the invention, the invention relates to the unique advantages associated with 1: 1 metal complex compounds used in dental compositions. As an example, the 1: 1 metal complex compounds according to the present invention are highly soluble and readily dissociate to allow metal ions to mineralize tooth tissue and / or in the pH range commonly encountered in the oral cavity. Make available to inactivate enzymes secreted by microorganisms. This is especially apparent in the application of the present invention where metal ions need to be introduced in large amounts into the gingival tissue. The pH range in the mouth is about 4
Since about 9 and generally about 7, the copper ions of the present invention are available at the pH encountered in the mouth. Thus, the present invention contemplates the release of large amounts of metal ions from soluble metal complex compounds at a pH of about 7 because the complex compounds are relatively unstable at about pH 7. These preferred
1: 1 metal complex compounds are very stable even at high alkaline pH and are relatively inert towards organic molecules. Moreover, as shown by the S-shaped appearance on the pM-pH diagram, they have unique dissociation physical properties.
The 1: 1 metal complex compound achieves the desired release of metal ions at pH where destruction of dental tissue, such as subgingival tissue, occurs. The present invention provides a unique system for making therapeutic metal ions available to tooth tissue in the form of a dental composition containing soluble, readily dissociable metal ions. Therefore, a feature of the present invention is the availability of metal ions in the oral cavity to impart minerals to tooth tissue and / or to inactivate enzymes secreted by microorganisms normally present in the oral cavity. To provide improvements in the art.

In another aspect, the dental composition according to the invention can be in different types of formulations such as solids, liquids, gels or pastes, which include toothpaste, dental creams or gels, toothpaste, liquids. Includes dentrifices, tablets, mouth rinses and others. In addition, the dental compositions of the present invention may contain suitable thickening agents, abrasives, flavoring agents and / or sweeteners to prepare the desired final product.

Accordingly, the particular features and unique advantages of the dental compositions and methods of use according to the present invention are that of various dental tissues to combat the unwanted destructive effects associated with the physiological parasitic bacteria present in the oral cavity. Make the treatment extremely effective.

The inventor of the present invention owns US Pat. No. 4,055,655
Nos. 4,129,509, 4,180,473 and 4,27.
We acknowledge that US Pat. No. 8,610 discloses metal complex compounds and methods of making the same. It has been found according to the present invention that these metal complex compounds are particularly surprising here to be effective in mineralizing tooth tissue. However, despite the fact that such complex compounds have been reported as effective antimicrobial agents and metal transport agents, it has not hitherto been known that they can exert their own effects in a dental composition for treating dental tissues, and That is. Furthermore, it is believed that these discoveries and other advantages of the invention described herein are unexpected and non-obvious.

The above and other features and advantages of the present invention, including various novel details regarding the method and the type of dental composition used in the method, will now be particularly further described with reference to the following detailed description. , Examples, drawings and claims. The methods and dental compositions embodying the invention are illustrated by way of example and are to be understood as being illustrative only and not limiting of the invention. The principles and features of this invention may be used in numerous and various aspects without departing from the scope of the invention.

For purposes of illustration to better appreciate the present invention, the following detailed description and examples are set forth for methods and methods for mineralization of tooth tissue and / or inactivation of enzymes secreted by microorganisms according to the present invention. It shows about a dental composition.

In a preferred embodiment of the invention, the dental composition according to the invention comprises a monometallic complex compound of a polyvalent heavy metal with a ratio of heavy metal to ligand of 1: 1 and a polyfunctional organic ligand, the complex compound being pM. -It has the dissociative physical properties shown by the S-shaped graph in the pH chart. Specific examples of metal complex compounds include disodium-, dipotassium- or dilithium-monocopper (II).
There is a dialkali metal monocopper (II) citrate represented by citrate. These dialkali monocopper (II) citrates have the dissociative physical properties shown in the S-shaped graph, where the bidirectional curves meet at points within the pH range of about 7 to about 9. In basic media of the order of about pH 9 to about pH 12, these dialkali monocopper (II) citrate complex compounds are very stable, i.e. effective stability constant K on the order of about 10 ¹² to about 10 ^13. It was confirmed to have an _eff value.
However, the K _eff of these dialkali monocopper (II) citrate complex compounds at a pH of about 7 to about 9 is about 10 ⁵ to.
It is on the order of about 10 ¹² . Therefore, the effective stability constants of these monocopper (II) citrate complex compounds decrease remarkably at pH around 7 (reduced to one thousandth to several tens of thousands).
And make a significant concentration of free Cu ⁺⁺ available for mineralization of tooth tissue. For example, about 10% of copper in complex compounds
Becomes ionic at or near pH 7, whereas pH 9
Or at about pH 9, about 0.1% of copper is ionized.

That is, it should be understood that the dental composition of the present invention is sensitive to pH, and as the pH decreases to about 7 or less, more copper ions become available. Is. Generally, the metal complex compound is about 3 to
It has a tendency to dissociate over a pH range of about 12. At pH's above about 12, this complex compound tends to be decomposed by the alkaline medium and precipitate from the medium in the form of hydrous metal oxides. The instability of this metal complex below about pH 7 is required for the implementation of dental tissue treatments in high concentrations of free Cu.
Bring ⁺⁺ . For example, the pH of the oral cavity in the human mouth typically varies within wide limits of about 4 to about 9 and is most effective at releasing metal ions. The complex compound is preferably dispersed in the vehicle so that the composition has a pH of about 4 to about 9, preferably about 7, to maximize release of the metal ion into the treated oral cavity.

According to this description and this preferred embodiment, metal complex compounds of other polyfunctional organic ligands correspond to the embodiments of the present invention as long as they exhibit the dissociative physical properties shown by the S-shaped curve on the standard pM-pH diagram. It will be obvious that it is. By way of example, monovalent or polyvalent, in particular divalent and polyvalent cations, based on the monometal-polyfunctional organic ligand complex compounds according to the invention, including aene, nickel, chromium, bismuth, silver, cobalt and especially copper. Other metal ions as well as other similar metal or heavy metal ions can be used. Other polyfunctional organic ligands can be used in place of the citric acid specifically exemplified by the preferred embodiment of the present invention. Among the other multifunctional ligands are the wide variety of alpha or beta hydroxy polycarboxylic acids of which the citric acid family is a member. Also, acids substituted with other functionalities such as alpha or beta amino, sulfhydro, phosphinol and the like can be substituted with the molecular model of the metal complex compound of the present invention and similar results can be achieved. From the general formula of the metal complex compound, the monometallic complex compound of copper and citric acid of the present invention corresponds to either of the following structural formulas (A) and (B): Form (A) is considered to be a preferred form from the viewpoint of free energy. One proton introduced into the complex structure shown in either (A) or (B) form prevents deformation of the stable 5- or 6-membered coordination ring. When a proton is introduced, only a 7-membered ring may be formed by the coordination of an acetate electron donor, and such a 7-membered ring structure is unstable. Accordingly, the complex compound molecules dissociate, providing metal ions that are mineralized to the tooth tissue.

Structural forms (A) and (B) can be more generally represented by the following forms: In the above type, the solid line portions represent chemical bonds between elements in the skeletal structure of the molecule, X, Y and Z represent electron pair donors, and (R) represents any elemental or molecular group or group. , M represents a metal, and the proton affinity of X is greater than that of Z, Y or R, thus oxygen, divalent copper or, for that matter, other Lewis bases instead of carbon atoms. Proton pairs and other metal ions are used for these structural types to show similar dissociation by the introduction of one proton, or pM
-It is recognized that it is possible to provide molecular forms that behave similarly, as shown by the S-shape modality in the pH diagram. Therefore, these molecular forms are alternatives to the complex compounds of the present invention.

The unusual configuration of the molecules of these copper complex compounds imparts a dipolar character to the compound, which is rather rigid and is characterized by hydration at either pole in a highly polarized manner. This feature causes hydrated complex compounds to be electrostatically adsorbed on the surface of finely divided particles having electronegative or electropositive surface characteristics. It also allows copper "entrapped" in complex compounds to migrate completely through membranes such as the cell walls of microorganisms. Although no direct proof of this complete migration has been obtained, all the aggregated results can provide an inductive reason for such a migration to occur. That is, this result shows that the complex compound containing the metal ion can move into the region where the similar compound is excluded. For example, when a copper salt is applied to a protein film, the copper ions form a copper protein compound or salt and attach to the film components. Although unlikely, if any of the copper ions are soluble and ionized, the availability will advance far beyond the oral cavity.

With reference to the description of the background of the invention, although conventional divalent metal complex compounds have also been incorporated into dental compositions, the metal ions in these complex compounds are very tightly bound, and (or ) Biochemically it is virtually impossible to utilize the metal ion to perform very useful functions because it is contained away from the recipient site. In contrast, the unique proton-induced dissociation properties of the complex compounds of the present invention make metal ions such as copper ions readily available as follows: Furthermore, the present invention 1: 1 copper complex compound in addition to having bipolar characteristics, most importantly, have a relatively weak structure constant _{(formation constant) (K f)} , the weak K _f value Means that copper acceptors with stronger K _f values can extract copper ions from the 1: 1 copper complex. This is accomplished in vivo by structures such as free amino acid groups, sulfhydryl groups, dental tissue hydroxyapatite and any Lewis acid capable of reacting with the coordination bond holding copper in place. That is, when a hydrogen ion is introduced into the system, a site for the introduced hydrogen ion instead of the free hydrogen atom, which was originally associated with the alcoholic hydroxy group of the citrate moiety, is formed. The complex compound is then destabilized. On the other hand, the complex compound of the present invention is characterized by having a proton-induced dissociation property. This property is important for the pharmacodynamics of the inventive copper complex and its use in the treatment of dental tissues.

As used herein, the term "dental tissue" includes tissues located in the oral cavity, such as subgingival tissue that is subject to enzymatic destruction by enzymes secreted by the teeth and the microorganisms present therein. Has meaning. The term "subgingival tissue" is meant to include tissues located below the gingival line such as roots, periodontal ligaments and body tissues. The term "disorder" has the meaning including, but not limited to, plaque and caries production, caries, bad breath and dental tissue deterioration. Accordingly, the present invention provides novel dental compositions and methods for treating dental tissue in animals. The compositions and methods of the present invention are particularly useful, for example, in reducing dental tissue and inhibiting plaque formation due to destructive enzymatic activity of enzymes secreted by microorganisms on dental tissue. This is achieved, for example, by the inactivation of enzymes and the addition of minerals to the dental tissue by the dental composition according to the invention. Furthermore, the compositions and methods of the present invention are useful, for example, when used in conventional preventative treatments, to inhibit tartar accumulation, particularly on teeth. Therefore, the metal complex compounds of the present invention can be advantageously used, for example, to prevent the accumulation of tartar and tartar on teeth and to reduce the destruction of subgingival tissues such as periodontal ligaments.

In order to achieve the above effects, the 1: 1 metal complex compound of the present invention is applied to the above-mentioned tissue in the oral cavity, and copper ion (CuII)
By forming a metal coordination complex or salt with a metal ion, such as, with hydroxy and fluoroapatite,
It can be used to add minerals to tooth tissue. For example, cupric-containing apatite (cupriapati) in tooth tissue
The formation of te) is particularly effective against enzymatic degradation and provides highly resistant complex compounds. Moreover, such mineralized tissue is less susceptible to the formation of unwanted plaque and tartar thereon. More importantly, periodontal ligament tissue is uniquely modified by the formation of such copper complex compounds on the surface of fibrils that are utilized for destructive enzymatic activity of gingival bacteria.

The pH in the human mouth, as described above, generally varies within wide limits, typically from about 4 to about 9, and is usually about 7. Therefore, in order to make the metal ion available for the formation of complex compounds or salts with anionic ligands of various structures and / or relative ions, the metal ion must be soluble in the pH range of the oral cavity and dissociated. It must be provided in a form that can. The 1: 1 metal complex compounds of the present invention, especially the complex compounds of copper and citrate, are uniquely suited to provide such materials. That is, the present invention makes highly soluble and easily dissociable metal complex compounds available for mineralization of tooth tissue via this unique delivery system.

In addition to forming complex compounds and salts that are resistant to enzyme attack, the metal complex compounds of the present invention provide metal ions such as copper that readily inactivate the host of enzymes capable of destroying tooth tissue. In this way, destructive enzymatic degradation of, for example, teeth and surrounding tissue is effectively reduced. Even if complete relief of all these subjects is not achieved, the dental composition of the present invention advantageously reduces the activity of destructive enzymes by enzymes secreted by physiological parasite microorganisms present in the oral cavity. Are suitable. That is, the 1: 1 metal complex compound of the present invention which provides a readily available metal ion such as copper ion (II) can be incorporated into the dental composition of the present invention so that both dentists and patients can use it. It can be used to advantage as a means to combat tooth loss.

In another aspect of the invention, tooth-like tooth tissue is
It has been found that treatment with a 1: 1 metal complex substantially reduces the formation of plaque or tartar on the teeth. This unique effect helps reduce or prevent the occurrence of caries.

Furthermore, the dental composition of the present invention, when prepared in the form of a liquid dentriflix or mouthwash, can be used as a deodorant or breath freshener, which substantially reduces halitosis by microorganisms present in the oral cavity. Can be made.

Normal whole soft tissue usually does not respond to the presence of the copper complex of the present invention, as evidenced by bleaching.
On the other hand, worn, infected and otherwise macerated tissues and granulation tissues show a slight blue-green bleaching. This is believed to be due to the many available coordination sites for these tissues undergoing either rapid alteration or rapid regeneration.

To prepare a preferred dental composition, the copper complex compound should be incorporated into the composition in an amount ranging from about 0.05% to about 5% (by weight), calculated on the copper ions of the total composition. Is. Preferably, this range is from about 0.1 to about 1% copper, and most preferably from about 0.2 to about 0.4% copper.

1: 1 copper complex compounds of the type particularly suitable for the supply of copper ions according to the invention are, as mentioned above, for example disodium-,
Dipotassium- or dilithium-monocopper (II) citrate and especially disodium-monocopper (II) citrate.

The dental composition of the present invention, in addition to these metal complex compounds,
Other suitable compounds such as thickeners and abrasives can be included. Suitable thickeners can be derived from various cellulose derivatives such as carboxymethyl cellulose. The amount of thickening agent incorporated into the dental composition can vary widely, for example in the range of about 1% to about 10% depending on the type of composition being prepared. For example, if the dental composition is in the form of a viscous liquid, less thickening agent may be added than if the composition is pasty. Therefore, as an example, the dental composition of the present invention can be made liquid, creamy or pasty depending on the amount of the thickener incorporated therein.

For the abrasive, for example, aluminum oxide, aluminum hydroxide, talc, pumice, dicalcium phosphate, etc. are most suitable. The amount of these abrasives can vary,
Generally from about 10% to about 50% (by weight) of the dental composition. However, it should be understood that the proper formulation of the abrasive is not a requirement of the invention. However, incorporation of an abrasive into the dental composition provides a scratching action on tooth tissue such as tooth enamel, which advantageously provides a more suitable surface for complexing metal ions.

In addition, any appropriate flavoring agent or sweetening agent may be added to the dental composition to season the dental composition of the present invention. Examples of suitable flavoring ingredients include, for example, aromatic oils such as spearmint, peppermint, deer,
Includes Satsusafras, cloves, sage, Eucalyptus, Majorana, cinnamon, lemon and orange extract, and other suitable flavors. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, sodium cyclamate, satsukarin, susparanate and the like. In preparing the compositions, these flavoring agents and sweeteners may be combined, such as from about 0.01% to about 1% of the composition.
Or more can be configured.

The dental composition of the present invention should have a practical pH. A pH range of about 4 to about 9 is particularly desirable, with a more preferred pH of about 7. This pH value means the pH of the dental composition. If desired, any suitable substance, such as citric acid, can be added to adjust the pH.

It should be understood that the above-mentioned dental composition can be modified in a number of ways. For example, the various ingredients in each product produced can be varied to a significant extent with respect to their properties and relative weight ratios and also physical properties in the formulation process. In the formulations referred to herein as dental compositions, certain combinations of components can be used as appropriate formulations depending on the application in the oral cavity. Such dental compositions can be in solid, liquid, gel or paste form and include toothpaste, dental creams or gels, toothpastes, liquid dent refixes, tablets, mouthwashes and the like. These products can be prepared by conventional methods. In preparing toothpaste, various solid components are mechanically and usually thoroughly mixed. Instead of various ingredients,
It should be understood, of course, that other suitable components having wholly or partly similar chemical or physical or physiological properties can be used.

In the case of a dental cream, gel or paste composition, the liquid and solid components should be combined in suitable proportions so as to form an extrudable mass with the desired viscosity. However, this viscosity should be suitable for use in extruded tubes or pressurized vessels lined with aluminum or lead, for example.

An example of a preferred liquid dental composition according to the present invention contains aluminum hydroxide, dicalcium phosphate, sorbitol, carboxymethylcellulose and water in suitable amounts in addition to the 1: 1 copper complex compound. Preferably, the amount of 1: 1 copper complex is that amount which provides about 4 mg of copper per ml. At this concentration, 5 drops of liquid composition contain about 1 mg of copper in the form of a 1: 1 copper complex. Therefore, the adult daily allowance for copper is almost 1
Since it is recommended to be mg, depending on the purpose,
It can be indicated that such a liquid composition is applied in an amount of at least about 5 drops. Although not recommended, it should be understood that inadvertent increases in the amount of copper are nontoxic.

When using a dental composition according to the present invention, the instructions for treatment with such a composition consist of applying the treatment at least once a day using a soft toothbrush or a suitable dental appliance. A soft toothbrush has the ability to penetrate into the gingiva starting with a trauma. Further, according to the present invention 1:
The one-metal complex compound can also be applied professionally, for example by a dentist or a dental hygienist, using conventional equipment. As an example, a 1: 1 metal complex compound may be used to prevent dental plaque or tartar build-up, and also to reduce or prevent the development of dental caries, by using a rubber mouth-to-mouth cleaning wick to prevent teeth from dripping. Can be applied to. However, prior to application, it is preferable to first remove tartar from the teeth, for example by means of a toothbrush and / or an ultrasonic tartar remover, in order to clean the tooth surface.

U.S. Pat.Nos. 4,278,610 and 4,180,473 by the present inventor
Nos. 4,129,509 and 4,055,655 are suitable for use in the dental compositions and methods according to the present invention 1: 1
A method for producing a metal complex compound and a method for measuring dissociation of such a complex compound are described. The entire descriptions of these US patents are incorporated herein by reference.

Production of Metal Complex Compounds and Dental Compositions The following methods are used to produce the dental compositions according to the present invention. In the following example, disodium-monocopper (II) citrate (MCC) is used. This copper citrate complex compound (MCC product) is produced as follows: Ingredients: Water 65 ml Citric acid, Anhydride 65 g Basic copper carbonate [CuCO ₃ · Cu (OH) ₂ · H ₂ O] 35 g Sodium bicarbonate (NaHCO ₃ ) 60 g Citric acid is dissolved in water. Add basic copper carbonate with stirring and disperse well. The mixture is allowed to react for about 10 minutes or until no bubbles (CO ₂ evolution) evolve. Add sodium bicarbonate gently while gently mixing to pH
To 5.5 to 6.0. The solution is mixed until a black granular precipitate is no longer visible [Cu (HCO ₃ ) ₂ ]. Add the rest of the sodium bicarbonate gently while gently stirring to 7.0.
Adjust to pH and store. The soluble copper chelate thus produced is free of secondary salts. Disodium-monocopper (I having a concentration of 100 mg of copper by weight per ml (I
I) A citrate (MCC) product is obtained.

Other techniques for making complex compounds are described in US Pat.
No. 278,610, column 5, lines 65-68 and column 6, lines 1-57, which are incorporated herein by reference.

In order to formulate MCC into liquids, creams, gels, pastes, etc., it is necessary to select the components very critically. MC
C has been found to be chemically incompatible with a number of substances. As mentioned above, the composition according to the invention must also have a pH which does not adversely affect the activity of the complex compound. It has been found that the pastes and liquid vehicles used with the metal complex compounds of the present invention in a unique and advantageous composition meet the chemical and incompatibility problems and aesthetic requirements of metal complex compounds such as MCC. It was Such vehicles include the following: Paste Vehicle Dibasic Calcium Phosphate 50 g Aluminum Hydroxide Gel 20 g Sorbitol 5 g Carboxymethyl Cellulose 3 g Peppermint Oil 0.1 g Water 21.9 g 100.0 g All of the above ingredients together. Combine and mix intimately to produce a smooth, homogeneous paste. This paste vehicle
100 g of the MCC product produced above (100 m of copper by weight per ml)
Mix well with 4 ml (containing g) to form a paste. An MCC toothpaste containing about 4 mg of copper per gram of toothpaste is obtained.

To 100 ml of the above-prepared MCC product containing 100 mg of copper per ml of liquid vehicle and MCC product is added sufficient amount of dipotassium hydrogen phosphate (about 0.5% by weight of liquid) to maintain a pH of about 7. The liquid produced is a liquid MCC dental product.

However, it should be understood that solid form of copper citrate can be used in place of the liquid MCC product described above to produce the MCC dental product of the present invention.

Example 1 Several human teeth extracted for treatment purposes are immersed in a 100% ethanol bath for 2 weeks to dehydrate the pulp cavity and preserve the integrity of the dental tissue. Formalin solution is commonly used for storage purposes, but formaldehyde is a well-known reducing agent and can cause the conversion or reduction of copper (II) by mechanisms other than the natural mechanism. Therefore, instead of formalin, absolute ethanol is used, which is a satisfactory alternative and is also customary for the purpose of preservation of biological specimens.

An electron microscope in combination with X-ray Energy Dispersive Analysis (EDAX) is used to determine the presence of copper in the tooth tissue. This method is a method of revealing the presence or absence of the number of atoms in the texture, especially in the surface texture. In addition, this method uses high vacuum, so dehydration of the tissue is essential, which requires the ethanol treatment described above.

Electron microscopy of this dehydrated tissue in combination with EDAX shows no apparent microscopic changes in teeth treated in this way. Under the scanning electron microscope (SEM), crystal structures are easily seen in the root region. SEM-EDAX is performed at 40,000x in these areas where there is no visible soft tissue residue. Inspect only crystalline material.

Since the cementum is a component directly adjacent to the body tissue of the jaw, its absence makes it unnatural for testing, so scraping or otherwise removing it from the lower elephantum. I can't recommend it. Cementum exhibits a degree of mineralization and hardness comparable to bone. The first difference between enamel, elegans and cementum is in the amount of calcium hydroxyapatite component.
Furthermore, because the cementum contains a greater amount of collagen than the elephant or enamel, it provides more potential binding sites for copper ions than the enamel crystalline material.

The treated teeth are reasonably conductive so that direct SEM inspection can be performed without the use of gold deposits or other coatings.

Figures 1 to 3 show three different areas of a tooth treated by first washing with distilled water, drying with a wash and then applying the liquid tooth composition with a soft toothbrush.
It is a figure which shows an EDAX spectrum. The liquid dental composition used in this case was prepared as described above and contained disodium monocopper (II) citrate in an amount of about 4 mg per ml. The above procedure was repeated on 6 other teeth with similar results.

More particularly, Figures 1-3 show various EDAX images of three different parts of the same tooth. The lower right central incisor is treated with the liquid dental composition from the midline to the anatomical right edge. The rest of the front of the tooth is not treated. A part of this tooth is treated with about 4 m of active ingredient, disodium-monocopper (II) citrate per 1 ml.
Exposure to a liquid dental composition containing g. Lightly brush the enamel surface for about 30 seconds. Soak the subgingival tissue for about 30 seconds using a swab containing disodium-monocopper (II) citrate. After the procedure, wash your teeth with plenty of tap water,
Then, it is dried with a tissue.

Figure 1 shows untreated enamel. The peaks due to phosphorus indicated by arrow A and calcium indicated by arrow B are clearly visible. The major calcium peak is due to K-alpha electron emission and the small peak is due to K-beta electron emission. No other elements are visible or observed.

FIG. 2 shows the treated surface of the same tooth, where the K-Alpha peak for copper, indicated by arrow C, is clearly visible, indicating that the copper was inserted into the tooth tissue. There is. As mentioned above, arrow A indicates phosphorus and arrow B indicates calcium. In addition, the computer generated mark system used to identify K-alpha and K-beta positions for copper was incorporated into this figure. This is indicated by E and F respectively.

In FIG. 3, the phosphorus shown by arrow A and cement shown by arrow B and calcium shown by arrow B of Kyozoite and cementum are shown as K- for copper shown by arrows C and D, respectively.
Shown with both alpha and K-beta peaks, indicating that large amounts of copper are intercalated in cementitious rather than enamel tissue.

Example 2 In this example, a series of patients confirmed to have severe calculus formation were treated with the metal complex compound according to the present invention. Generally, for this medical treatment, the active ingredient, disodium-monocopper (II) citrate (MCC), CAS Registry Number: 65330 in an aqueous vehicle containing aluminum hydroxide, dicalcium phosphate, sorbitol, carboxymethylcellulose and water. A composition is used in which -59-8 is dispersed to form a paste. In all cases used here by way of example, the usual examination techniques by dentists, ie physical examination etc., are carried out and diagnostically confirmed. The age of the patients involved in this case ranged from 35 to 73 years.

All patients in this example are self-treatment prior to treatment with the metal complex of the present invention. In self-treatment, all patients brushed with standard dentifrice at least once a day, treated with dental floss, and then applied a mixture of baking soda, saline and water to suppress or control tartar accumulation. did. Following self-treatment or in combination with self-treatment, each patient was given a conventional tooth scraping procedure with a pandpick or ultrasonic scaler and a mixture of pumice and stannous fluoride with a rubber tooth mouth cleaning suction angle. Underwent a standard treatment course by a specialist including mechanical tooth brushing. The patient in this example received treatment every 3, 4 or 6 months, and had a dentist's standard treatment duration of about 4 to about 12 years.

At the time of the first examination by the dentist, each patient's mouth was in very poor condition, with gross accumulation of tartar. However, there are no cavities or restorative teeth.
After standard professional treatment, the oral condition of each patient showed signs of slight improvement in calculus accumulation and only slight improvement.

Treatment with standard technicians was followed by treatment with MCC on all sides of the 6 lower anterior teeth, which was performed by the dentist every 10 months for a total of 3, 4 or 6 months. Treatment consisted of initial handpicking of the six lower anterior teeth and tooth debridement by scraping with an ultrasonic scaler, followed by mechanical brushing of the tooth with the MCC mixture applied with a rubber toothpaste cleaning angle. After experimental treatment with the inventive copper complex, a dramatic reduction in tartar deposits on the 6 lower anterior teeth was seen in all patients compared to the rest of the teeth treated with standard treatment. The overall appearance of the 6 lower anterior teeth was excellent.
However, two patients complained of metallic taste from the MCC mixture, which disappeared shortly after rinsing. The more detailed results of this example are shown in the table below.

Thus, it can be seen from these examples that the dental composition and the method for using the same according to the present invention are effective for treating and mineralizing tooth tissues including teeth and subgingival tissues. As a result, the dental compositions of the present invention provide a unique and previously unattainable means of making metal ions available in the oral cavity to reduce or prevent dental tissue loss and tartar accumulation.

Of course, the present invention may be practiced in other ways than those described herein without departing from the spirit and essentials of the invention. Therefore, in all respects, the above-mentioned aspect is for explanation and is not restrictive, and all the modifications included in the meaning equivalent to the scope of claims are included in the present invention. Included.

[Brief description of drawings]

FIGS. 1 to 3 are graphs showing EDAX spectra at three points of a tooth, FIG. 1 is an untreated enamel, and FIG. 2 is an enamel and elephant treated with the dental composition of the present invention. And cement quality, respectively.

Claims (10)

[Claims] 1. A dental composition for treating dental disorders including halitosis, caries, decay of tooth structure, tartar accumulation, and plaque formation, wherein the composition comprises a polyvalent heavy metal ion and an organic compound as active ingredients for teeth. A 1: 1 ratio of a monometallic complex compound with a polyfunctional organic ligand selected from the group consisting of acids and substituted organic acids and a therapeutically acceptable aqueous vehicle for such active ingredients, The complex compound has an aqueous proton-induced dissociation physical property indicated by an S-shaped curve when the negative logarithm of metal ion concentration vs. negative logarithm of hydrogen ion concentration is plotted in Cartesian coordinates, and the composition is a tooth. A dental composition which is administered in an effective amount to the structure of claim 1 to release the metal ions at a pH in the range of about 4 to about 9 to treat the dental disorder. 2. The dental composition according to claim 1, wherein the monometallic complex compound comprises a polyvalent heavy metal ion selected from the group consisting of copper and aene complexed with α-hydroxypolycarboxylic acid. . 3. A monometal complex compound comprising dialkali metal monocopper (II) citrate and dialkali metal monoaene (I
The dental composition according to claim 2, which is selected from the group consisting of I) citrate. 4. The polyvalent heavy metal ion is selected from bismuth, chromium, cobalt, nickel, silver and mixtures thereof.
The dental composition according to claim 1. 5. The method according to claim 1, wherein the substituted organic acid is selected from the group consisting of hydroxypolycarboxylic acid, aminopolycarboxylic acid, sulfhydropolycarboxylic acid and phosphinol polycarboxylic acid. The dental composition described. 6. The dental composition according to claim 1, wherein the vehicle is selected from the group consisting of an aqueous liquid, an aqueous gel, an aqueous cream and an aqueous paste. 7. The dental composition according to claim 6, wherein the vehicle comprises a proper amount of an abrasive, a sweetener, a thickener and water. 8. The dental composition according to claim 7, wherein the vehicle comprises aluminum hydroxide, dicalcium phosphate, sorbitol, carboxymethyl cellulose and water. 9. The method of claim 3 wherein the dialkali metal monocopper (II) citrate or dialkali metal monoaene (II) citrate is present in an amount of about 0.05 to about 5% by weight of the composition. The dental composition described. 10. A composition comprising about 0.4% by weight of disodium monocopper (II) citrate or disodium monoaene (II) citrate and aluminum hydroxide, dicalcium phosphate, sorbitol, carboxymethyl cellulose. The dental composition according to claim 1, comprising an aqueous vehicle consisting of: and water.