DE2156491A1 - Preparations containing organic polymeric polyphosphonates and their use for dental treatment - Google Patents

Description

Preparations containing organic polymeric polyphosphonates and their use for dental treatment

The invention relates to preparations containing organic polymeric polyphosphonates and their use for dental treatment.

Polymeric polyphosphonates are known compounds for several manufacturing methods are described. An al-1 common Applicable method for the preparation of polyphosphonates is described by Schroeder and Sopchak in "The Reaction of Phosphorus Trichloride and Oxygen with Polymers ", J. Polymer Sci., 47, 417 (1960). In this process, oxygen is used blown through a solution of a polymer in boiling phosphorus trichloride and the course of the reaction by titration of the escaping HCl is determined. After distilling off the phosphorus trichloride and the phosphorus oxychloride, the reacted Polymer dissolved in a solvent such as toluene and hydrolyzed by adding water. the

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precipitating water-insoluble polymeric polyphosphonic acids can by reaction with, for example, aqueous Alkali or ammonium hydroxide can be converted into water-soluble salts. The cleaning can, if necessary, carried out by re-acidifying the salt solution with hydrochloric acid, washing the precipitate in water and drying in vacuo will.

_fc It has now been found, completely surprising, that when certain organic polymeric polyphosphonates are applied, preferably in the form of the mono- or di-alkali salts or ammonium or substituted ammonium salts, the formation of a firmly adhering protective layer on the tooth enamel can be achieved The polymer coating that has arisen from the enamel is present in a monomolecular layer and is therefore so thin that it is practically invisible. In spite of this, the coating prevents adhesion and growth

P of bacteria on the tooth enamel and therefore protects the tooth surfaces against tooth decay and plaque formation. Furthermore, was found that the phosphonate groups in the polymers create a firmly adhering bond between the S-hnschmelz and the polymer coating is created, which cannot be removed by abrasion. The bond created in this way will also not attacked by enzymatic hydrolysis and is therefore

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relatively stable under the physiological conditions present in the oral cavity.

There are therefore proposed with the invention formulations having a content of organic polymeric polyphosphonates, which are characterized in that they are "at least a content of 0.01 wt.% Of an organic polymeric polyphosphonate having a molecular weight of at least 1,000 and a carbon-phosphorus ratio of at least 2 : 1 in a compatible non-toxic carrier The invention further proposes the use of these preparations for dental treatment, the tooth enamel being treated with an orally administered solution, paste, powder or slurry containing organic polymeric polyphosphonates.

According to the invention, the organic polymeric polyphosphonate salts applied to the surfaces of the teeth in a suitable carrier. Water, water-ethanol mixtures can be used as carriers or other liquid solvents are used; in these cases the resulting preparation either brushed on the teeth or used in the form of a mouthwash. As a carrier, however, can also Toothpastes of the usual kind are used, whereby the polyphosphonates come into contact with tooth enamel; Tooth powder can also be used as a thin liquid after adding water or saliva Slurry or paste can be brushed onto the tooth surfaces. 209823 / .1094

Since only very small amounts of the organic polymeric phosphonates are required to produce a monomolecular layer on the enamel of all teeth (generally less than 1 mg is required for all teeth), excellent results are achieved in all forms of application as a solution, paste or otherwise preparation form obtained when these preparations only 0.05 wt.% of _{polyphosphonates?} corresponding to about 0.5 mg per ml of the coating solution! or if they contain only 0.01 wt. ^, as in Example 2. If desired, the concentration of the polymeric polyphosphonates in the preparations can also be greater, to about 5 wt.% Or more, to be. At higher concentrations, the time required for the treated enamel surfaces to become saturated with the polymer is reduced. In all cases, however, regardless of the concentration of the polymer in the preparation, the adsorption is complete within 15 to 10 hours and the unadsorbed residual portion of the polymer P can then be removed from the oral cavity. At very low concentrations, the preparation must act on the teeth for several minutes before it can be removed again.

Polymeric polyphosphonates can be obtained by the method already described by Schroeder and Sopchak; after this Processes can also include numerous polyphosphonates to be used according to the invention, such as, for example, polyphosphonates of

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polymerizable unsaturated ethylene monomers, polyesters or cellulose acetate. Preference is given to using non-crosslinking polymers such as for example polyalkanes such as polyethylene, polypropylene and polybutadiene, polyethylene tekphthalate and others Polyesters, polyacrylates and polymethacrylates, polystyrenes, polyamines, copolymers of acrylic and methacrylic esters, Polyvinyl butyral resins, polyvinyl acetate and cellulose acetate. These organic polymers can optionally with substituents that do not affect the effect, such as, for example, alkyl, halocarboxyl or sulfonate groups be substituted.

Polymeric polyphosphonates can also be produced by another process in which polymerizable phosphonate monomers such as vinylphosphonic acid CH ₂ = CH-P (X ₅ Hp are reacted with other polymerizable groups to form a polymer with a large number of phosphonate groups Rochlitz and Vilcsek, Angew. Chem. Jh_, 9 ^ 0 (1962) by reacting a mixture of ethylene and oxygen with phosphorus trichloride in dichloromethane at -80 ° C. The monomeric vinylphosphonic acid can then, for example, with methyl methacrylate or ethylene dimethacrylate , Tetraethylene glycol dimethacrylate, dimethylaminoethyl methacrylate or the reaction product of bisphenol A and glycidal methacrylate can be copolymerized to form a polymeric polyphosphonic acid

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-D-

Vinylphosphonic acid, for example, also to form a homopolymer are processed.

With the methods described, organic
Prepare polymeric polyphosphonic acids containing 5 to about 25 weight percent phosphorus. Typical compounds contain 1 phosphorus atom for an average of 3 to 15 carbon atoms, whereas homopolymerized vinylphosphonic acid contains 1 phosphorus atom for 2 carbon atoms.

The water-insoluble organic polymeric polyphosphonic acids are applied to the tooth enamel in the form of their water-soluble salts with alkali metals r *, ammonia or amines
applied. These salts are readily soluble in water; the sodium or potassium salts are preferably used
in most cases the sodium salt is used. The polymeric polyphosphonic acids can be converted into their salts _} in which the insoluble acids in finely divided form in a
aqueous solution of, for example, sodium hydroxide, potassium hydroxide or ammonium hydroxide. If the salts of the polyphosphonic acids are prepared under approximately neutral pH conditions, such as at a pH of 5.0 to 7.5, only the monosalts of the phosphonic acids are formed; at a pH of about 8 or above, disalts are formed. The salts are preferably prepared in such a way that a solution of the basic compound is slowly added dropwise to a stirred suspension of the polymer,

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until the polymer dissolves. The pH value is then approximately pH 7 + 0 * 2, after the solution has entered it can until the desired pH value is reached, which is usually a physiological pH value of approximately 7 * 2 + 0.2 corresponds, further basic compound can be added.

For the sake of simplicity, the salts are the organic polymeric polyphosphonic acids referred to as polyphosphonate polymers or polyphosphonates in the further description.

Of the polyphosphonates which can be used according to the invention, polyalkene polyphosphonates are preferably made from, for example Polyethylene, polypropylene or polybutadiene are preferred. The polymers can have a molecular weight of over 1,000 to 100,000 or more.

The following examples are intended to explain the invention in more detail.

example 1

Polyethylene polyphosphonate (PP) was produced in a closed reaction vessel using phosphorus trichloride marked with F ^ , polyethylene and oxygen. The preparation of the polymer marked with P ^ allowed the localization of the polyethylene polyphosphonate described in Example 2 after application to tooth enamel. at

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the representation of the polyethylene polyphosphonate 36 mg P ^ -phosphorus trichloride a specific activity of 34.4 mC per mmol were distilled under vacuum in the reaction vessel, which already with 130 mg (0.9 mM) polyethylene (average MW 3,500) corresponding to a Content of 9.3 mM CHp groups. Then 1.5 g of unlabelled phosphorus trichloride were distilled into the reaction vessel and the mixture was heated to 80 ° C. to dissolve the polyethylene. The homogeneous solution of the polyethylene in PCI., Was then frozen out in liquid nitrogen, 7 * 5 mM oxygen was then condensed in the reaction vessel, the vessel was sealed and slowly warmed to room temperature. The oxygen pressure rose to approximately 6 atm. The reaction mixture heated up spontaneously during the exothermic reaction and was kept at a temperature below 60 ° C. with constant shaking. As the reaction proceeded, the solution turned brown; After approximately 10 minutes, the exothermic reaction was completed main and the reaction vessel was heated to complete the reaction I5 minutes in a water bath at 7O ⁰ C. The mixture was then frozen in acetone dry ice and the oxygen and HCl that had not been consumed were drawn off from the reaction vessel. A further 7 * 5 mM oxygen was distilled into the reaction vessel and the closed reaction vessel was heated again. After the mixture of HCl and Op had been distilled off a second time, the reaction mixture was warmed to room temperature and excess PCI and POCl.,

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distilled off in vacuo. The last traces of PCI, and POCl- were removed by leaving the reaction vessel was immersed in a 100 ° C water bath in vacuo.

The brownish solid residue containing $ 20

^ 52

15 ml of IN sodium hydroxide were added to the P ^ activity used. After digestion on a steam bath for one hour, the mixture was centrifuged off and the slightly brownish colored alkaline supernatant liquid containing 12% of the P ^ activity used was separated off, acidified with HN perchloric acid and centrifuged off. After centrifugation, the precipitate was redissolved in 10 ml of 1N sodium hydroxide, again precipitated with perchloric acid and centrifuged off. After the supernatant liquid had been removed after centrifugation, the polyethylene polyphosphonic acid precipitate was washed with water, dissolved in the smallest possible amount of 0.1N sodium hydroxide and adjusted to a pH of 7.5. The solution prepared in this way contained approximately 2% of the total activity used. By repeating the polyethylene polyphosphonic acid twice, an end product was obtained in which only 1% of the radioactivity present was in the form of inorganic phosphate. The effectiveness of the separation is based on the excellent water solubility of the phosphoric acid and the relatively low solubility of the polymeric phosphonic acid.

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As a final product 60 mg monosodium polyethylene polyphosphonic% of phosphorus were (PP) having a content of 12 wt. Obtained which had about a phosphonate group to an average of 6 to 7 carbon atoms. The end product had a specific activity of 25 AiC per mg of phosphorus.

Other polyphosphonates that can be used and can be produced by this process are:

I. Sodium polyethylene polyphosphonate with

a) an average molecular weight of 7,000 and a content of Ij5 # phosphorus accordingly one phosphonate group to 5 carbon atoms or 56 phosphonate groups per molecule or

b) with a molecular weight of 2,000 and a content of 18 # phosphorus accordingly one phosphonate group on every fourth carbon atom or 15 phosphonate groups per molecule.

II. Homopolymeric sodium vinyl phosphonate with a molecular weight of 20,000.

III. Copolymers of vinyl phosphonic acid as the sodium salt and - methyl methacrylate in a molar ratio of 2: 1 with a molecular weight of 15,000.

The polymers (a) and (b) were in a neutral to pH 7 * 1 to 7, j5 adjusted normal saline solution and dissolved this Solutions were applied interperitoneally to rats.

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No mortality of the rats was found in these experiments; all animals appeared during the experiment to be in good health. No hematological changes or changes in the chemical composition of the blood determined, on histological examination no pathological Changes in organs such as the heart, lungs, kidneys, liver, or adrenal glands are detected.

Example 2

Solutions of polyethylene polyphosphonate (PP), which was prepared as described in Example 1, were applied to the crowns of one-year-old bovine front teeth. The bovine teeth were obtained from Epoxilite Corp., Los Angeles, California and stored under water at 10 ° C. Before the experiments described, all cut or damaged surfaces of the teeth were ^{coated with a clear epoxy resin (Borden 1} s) after drying and, after drying for two hours at room temperature, stored in water for a further forty-eight hours before carrying out the experiments.

The teeth were then placed in aqueous solutions (pH 7 * 3 to 7.5) with different contents of polyethylene polyphosphonate at room temperature for different periods of time. Do washing with distilled water and drying the teeth, the absorbed activity was measured in a ScintiHations-

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counter measured with NaJ activated with thallium. As control tests experiments were carried out with P- ^ labeled phosphate ions and Cl ^ - labeled chloride ions carried out. In further experiments, the reaction rates of the desorption by immersing the with labeled polyphosphonate, phosphate or chloride Measure teeth in solutions of the corresponding unmarked compounds.

P The uptake of the polyethylene polyphosphonate was examined at three different concentrations; 0.001 N (equivalent weight 150, 0.15 mg / ml), 0.01 N and 0.0 ^ N, treatment times 10, 20, 30, 60 and 180 minutes. The half-value of the absorption rate of a 0.001 N solution was "J6 minutes (t. / P), with an absorption saturation of 1.9 x 10" - ^ / U mol per tooth being achieved. 0.5 cm)

a value of 49 + 9, \ i g PP / cm "of tooth enamel is obtained. For 0.01 N and 0.0 ^ N solutions of PP, half-values of the reaction rate of t ... " ~ ¹ ^ ^or 8 minutes and

Saturation absorptions of 32 + 8 and 6k + 12, around g PP / cm, were found. The kinetic behavior and the uniform absorption of a certain amount of the compound indicate that a monomolecular absorption layer of the polyelectrolyte is formed.

The comparison tests with phosphate ions in 0.01, 0.0 ^ and 0.1 N solution gave half _{values t, y 2} = 128.97 and 120 minutes, respectively

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2156431

and extrapolated saturation values of 3.2 10 ", 6.0 χ 10 and 17.5 χ 10 "/ U mole per tooth. The phosphate exchange capacity of a tooth that is not fully reached even in a 0.1 N phosphate solution is a thousand times larger than the absorption capacity for PP and thus also indicates the monomolecular absorption of the polyethylene polyphosphonate there. Comparative experiments with Cl gave half-values of the reaction rate of t, / p = 56 * 5 ^ or 55 minutes for 0.01 N, 0.03 N and 0.1 N Cl "solutions. The extrapolated absorption saturation values were 0.45, 0.33 and 1.1 / U mol per tooth and are therefore also two hundred up to six hundred times higher than the figure obtained for polyethylene polyphosphonate.

In the desorption tests, only a small amount of desorption of polyethylene polyphosphonate in distilled water, namely less than 10 % in 120 minutes, could be demonstrated. When teeth coated with PP were treated with a 0.03 N PP solution, a 30 ^ was obtained -y desorption in minutes and a 52 ^ -y in twelve hours. Comparative experiments with labeled phosphate in a 0.1 N phosphate solution showed an 8 ^ desorption in water / water in 120 minutes, a 55 ^ desorption in 120 minutes and a 90 ^ desorption in twelve hours. Immersion of teeth treated with PP in a 0.1 N phosphate solution resulted in a titanium desorption of less than 15 $ PP in twelve hours. By vigorous, thorough rubbing with a soft

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Cloth (Kimwipe tissue) could be 'of the adsorbed labeled compounds only 1% of the PP-type, J $ remove the phosphate activity and 6% of the chloride type.

The results obtained from these experiments show that polyethylene polyphosphonate strongly affects tooth enamel is adsorbed, probably as a monomolecular layer. The formation of a monomolecular layer P of a polyelectrolyte with a hydrophobic skeleton leads to an inhibition of the adhesion and the growth of Bacteria on the enamel treated in this way.

The enamel surfaces of the teeth should be clean and as far as possible be possible without bacterial deposits before a polyphosphonate polymer is applied to the teeth. This is particularly important for the first order, as the following more or less regular and periodic fc treatment of the teeth with the connection to the tooth surfaces stay clean and brush or brush less intensely before applying the new layer of polyphosphonate other cleaning is required. By applying an excess of fresh solution to the surface The polyphosphonate polymer on the already coated teeth is replaced by the newly absorbed polyphosphonate take place on the enamel surfaces against the existing layer, the tooth surfaces of any Discoloration that has solidified in the old layer

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BATH t

or liquid foods, smoking or the like can be exempted. Discoloration and stains are therefore removed before they can be seen with the naked eye. When using the polyphosphonate polymers as a component of, for example, toothpastes or tooth powder, results from the use of these tooth cleaning agents in the usual way a clean enamel surface. Other preparations can also be used accordingly are used with a content of polyphosphonate polymers such as mouthwashes, the use of such Preparations should only take place after the teeth have been cleaned, for example by brushing, to achieve clean, non-discolored enamel surfaces.

The polyphosphonate polymers used according to the invention are not toxic to mammals. Because of the size and the strong negative charge of the polyphosphonate polymer molecule, an electrolyte, so the compound becomes even after Ingestion, not absorbed in the human gastrointestinal tract.

Polymeric phosphonates show advantages over organic diphosphonates of the general formula RR'C (P0, H ~) ₂ or polyphosphonates with a low molecular weight. The adsorption of the polymer on the calcium apatite crystals is much stronger; they form a far more effective hydrophobic layer, the properties of which can be influenced by suitable copolymerization. Compared to diphosphonates are also less

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Bacteria absorbed on the teeth. In contrast to the The polymeric polyphosphonates, as highly negatively charged polyelectrolytes, cannot absorb diphosphonates from the gastrointestinal tract absorbed and therefore not taken up by living cells. The polymeric polyphosphonates provide thus do not pose a toxicological problem, even if they are used daily as part of a toothpaste.

»The primary polyphosphonates can be incorporated into various types of preparations for dental care, provided it is ensured that suitable and effective preparations result from a suitable selection of the other ingredients. Tooth cleaning agents in the form of pastes, powders or tablets are produced with a tooth-compatible, water-insoluble polishing agent as the main component, namely in amounts of approximately 10 to 98% by weight. The polishing agent is mostly 70 to 95 wt.% In tooth powders and 20 to 75 wt. % In tablets or toothpastes or Zahncrenfö.

Dicalcium phosphate, Tricalcium phosphate, calcium pyrophosphate, insoluble sodium metaphosphate, aluminum hydroxide, magnesium carbonate, silica gel, Calcium sulfate, bentonite, thermosetting synthetic resins or mixtures of these compounds can be used. The invention Preparations are preferably mixed with a polishing agent that does not release calcium ions in such quantities that this adversely affects the polymer.

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Except a polishing agent containing tooth-cleaning formulations in powder, tablet or paste form for the most part to 5 wt. ^ Of a nonionic, cationic or anionic surfactant such as sodium N-lauroyl sarcosinate, or sodium lauryl sulphate and sufficient amounts of a fluoride ion-containing compound such as Na ₂ FPCL, NaF or SnFp, which provide a fluoride ion content of 0.05 to 0.15 % and preferably 0.1 ^ in the end product.

To produce toothpastes, the polishing agent, the polymer in amounts of, for example, 0.25 to 2% by weight, and optionally auxiliaries, are mixed in a liquid carrier made from water and a humectant such as glycerine, propylene glycol or sorbitol. The liquid will generally comprise 20 to 75 wt.% Of cream. The content of humectant is in general from 10 to 40 wt.% Of Zancremej such toothpastes preferably contain from 0.5 to 10 wt.% Of a gelling agent such as natural and synthetic gums or gum-like compounds such as Irish moss, gum tragacanth, sodium carboxymethylcellulose, starch and similar Links.

Mouthwashes or rinses generally contain an effective amount of the polymer such as for example aqueous-alcoholic 0.02 in a flavored to 1% by weight of solvent having a content of 2 to 70 and preferably 5 -. 40 wt $ 6 of an alkanol having 2-3 C. Atoms such as

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Ethanol. In general, smaller amounts of a surface-active compound such as, for example, are also used nonionic surfactant added.

Other preparations suitable for dental care, such as, for example, to be used prophylactically by the dentist Polymeric polyphosphonates can be added to pastes, chewing gum, lozenges and the like.

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Claims (7)

Claims 1. Preparations for use in dental treatment, characterized in that it has a content of at least 0.01% by weight of an organic polymeric polyphosphonate having a molecular weight of at least 1 000 and a carbon-phosphorus ratio of at least 2:. 1 in a compatible non-toxic carrier exhibit. 2. Preparations according to claim 1, characterized in that it contains from 0.01 to 5 wt% of a polyphosphonate with a carbon-phosphorus ratio of at least J5: l in solution ·, Aufschlämmung- or paste form for application to the enamel surfaces of the teeth.. 3 «Preparation according to claim 1 and 2, characterized in that that the preparation is a toothpaste or toothpaste. 4. Preparation according to claim 1 to J5 »characterized in that that the polyphosphonate has a molecular weight of 1,000 to 100,000 and a carbon-to-phosphorus ratio of 3: 1 to 15: 1 and a polyphosphonate of polymerizable unsaturated ethylene monomers, polyesters or cellulose acetate. 5. Preparation according to claim 1 to 4, characterized in that that the polymer is a polyethylene polyphosphonate. 209823/1094 .20- '2156401 received amJiLjLlLi? ■> ^ - 'η 6. Preparation according to claim 1 to 4, characterized in that the polymer is a polyvinyl phosphonate. 7. Preparation according to claim 1 to 6, characterized in that that the polyphosphonates are in the form of their alkali or ammonium salts. 209823/1094 ORjgjnal fNSPECTED