DE2748570A1 - CALCIUM INHIBITION PREPARATIONS - Google Patents

Description

DR. BERG DIPL-ING. STAPF DIPL-ING. SCHWABE DR. DR. SANDMAIR

PATENT LAWYERS 2/4 8 5 7 Q

P.O. Box 8602 45, 8000 Munich 86

Attorney's file 28 493 2 c. GKT.! ¹ ;

Be / ßch

Monsanto Company St. Louis, Missouri / USA

"Preparations for inhibiting tartar"

This invention relates to "oral preparations" which are to be understood as meaning products which are delivered into the oral cavity in such a Were introduced so that they come into contact with the tooth surfaces therein. Examples of such Products include foods suitable for humans and animals, including chewing gum and oral hygienic products Mouthwash, pastes for prophylaxis, locally applicable

(0 (9) 988272 Mauerkircherstr. 45 - 8000 Munich 80 Banks: 9882 73 Telegrams: Bayerische Vereinsbank Munich 453100 988274 BERGSTAPF PATENT Munich Hypo-Bank Munich 3890002624 983310 TELEX: 0524560 BERG d Post check Munich 65343-808

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solutions and dentifrices such as toothpastes, tooth powders, toothpastes and the like.

Tartar, sometimes referred to as plaque, is a buildup that is predominant on the surfaces of teeth forms at or near the gum line. Tartar Above the gingiva occurs most strongly on the surfaces near the secretion openings of the salivary glands. Older tartar contains an inorganic part, which largely consists of calcium phosphate which occurs in a hydroxyapatite crystal lattice structure, similar to that found in bones, tooth enamel or dentin occurs. Furthermore, there is typically an organic part that contains used epithelial cells, saliva deposits, Contains leftover food, various types of microorganisms, etc.

As tartar develops, it becomes noticeable white or yellowish if it is not soiled or discolored by some foreign substance. Besides the fact that If this is undesirable for aesthetic reasons, older tartar deposits are the cause of gingivitis and are therefore a factor contributing to gingivitis and others Diseases of the tooth-bearing parts, the inflammation contributes to the resistance of the tissues to endogenous and exogenous Organisms decreased.

Periodic mechanical removal of this material by a dentist or dental technician is routine in the art. It has also been suggested a number

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to use chemical agents to remove tartar. For example Alkali metal and ammonium glycolates and there are the diglycolates of organic bases such as urea, guanidine or ethanolamine suggested for this use in British Patent 995,330. In the French patent specification 2,108,827 it is stated that the calcium ion sequestering ability of sodium glyconate to remove can be used by dental plaque. In U.S. Patent 1,516,206 it is described that a calculus-removing Effect through the use of an aqueous solution of a lactone or anhydride of a weak organic hydroxy acid, like galactonic acid, along with a weak organic one Acid, such as maleic acid or citric acid, is achieved and it is pointed out in U.S. Patent 3,429,963 that tartar can be removed by using dental preparations that are a hydrolyzed copolymer of ethylene and maleic anhydride having an average molecular weight of at least about 1,500.

In some cases, chemical agents are said to be useful in retarding tartar formation. So is in U.S. Patent 3,4-29,963 discloses that a reduction the formation of tartar in rats was observed when the drinking water administered to the rats was 1 # hydrolyzed copolymer of ethylene and maleic anhydride. In the aforementioned British patent specification 995 330 it is stated that a reduction in tartar formation can be achieved by using toothpastes containing certain diglycolates, achieved. Another polymer, i.e. a polyester one

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Polycarboxylic acid with three or more carboxyl groups and a polyalkylene ether with at least two hydroxyl groups is than Calculus retardant in U.S. Patent 3,542,91? described. In U.S. Patent 3,920,837 stated that the formation of tartar can be reduced by cyclohexane hexacarboxylic acid or its water-soluble salts can and British Patents 1,373,001 and 1,373,003 teaches to reduce tartar formation can be used when using a dentifrice containing a sparingly water-soluble zinc salt, e.g. zinc citrate, contains. Various compounds of phosphorus, such as ethane-1-hydroxyl-i.i-diphosphonic acid, were also used (hereinafter UHDP) proposed for such use in U.S. Patent 3,488,419.

Some of the previously proposed chemical agents for removing tartar or retarding its formation contain functional groups of indefinite action on living things in terms of toxicity, side effects, etc. Of certain other types of compounds that only Containing carbon, hydrogen, oxygen and possibly pharmaceutically acceptable cations may be accepted that they are essentially free of such uncertainties and are therefore preferably used in oral preparations. Compounds having a relatively simple structure are also desirable for the present purposes and low molecular weight, as well as compounds which can be prepared without carrying out a polymerization process. Accordingly, there are oral preparations that combine

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contain fertilizers that meet these criteria and essentially inhibit tartar formation, it is particularly desirable and it is an object of this invention to provide such preparations to provide. Another object is a method for inhibiting tartar formation using such preparations.

This invention relates to an oral preparation useful for inhibition effective for tartar formation, the preparation comprising:

1) a propanedioic acid (malonic acid compound), namely of Acids of the general formula

GOOH COOH

I I

X-C-O-C-Z

I I

COOH Y

wherein X -H, lower normal alkyl and / or HO

-CO-

Y is -H, -COOH and / or lower alkyl, with the proviso that

Y is -COOH when X is lower normal alkyl and Y is not -COOH when X is -H,

Z is -H and / or lower alkyl, with the proviso that Z is -H or lower normal alkyl, when X is lower normal alkyl, each of the radicals A and B, independently of the other, is -H and / or lower alkyl and η << 1 or 2 ,
as well as physiologically acceptable salts of these acids and

2) a carrier suitable for use in the oral cavity, with the compound in the formulation in an amount and concentration is present that is sufficient for the formation of

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- ^ - 27A857Q

To essentially inhibit tartar.

As used herein, the term "lower alkyl" means C ₁ -C 4 -alkyl groups which can be branched (e.g. isopropyl, isobutyl or tert-butyl) or cyclic (cyclopropyl or cyclobutyl), but preferably straight-chain (methyl, ethyl , n-propyl or η-butyl). "Lower normal alkyl" is to be understood as meaning straight-chain C * -C ^ -alkyl groups.

If η «2 in the preceding formula, the through A and B represented substituents on one of the carbon atoms are, where they connect the hydroxy and malonic acid groups in this formula, the same or different be of the A and B substituents on the other Carbon atom and connect such groups.

In a preferred embodiment of the invention, X is lower normal alkyl, Y is the group —COQH and Z is hydrogen or lower normal alkyl. In this embodiment, ea is preferred that Z is hydrogen, methyl or ethyl. Furthermore, in this embodiment it is preferred that X is methyl or ethyl. In a particularly specific embodiment, Z is preferably hydrogen or methyl and in this embodiment X is preferably methyl.

The compounds in the preferred embodiment described above, where X is methyl, Ϊ the group -COOH and Z is hydrogen or methyl, are here as methyloxy-bis- (malonic acid) or dinethyloxy-bis (malonic acid). These two

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_ _r _ 2 7 A 8 5 7

the specific acids are followed for convenience referred to as MOBPDA or DMOBPDA. The tetrasodium salts of these two acids and their variations when X and / or Z is ethyl can be prepared by the method described in U.S. Patent 3,865,755 which is referred to here. The tetrasodium salts of acids in which Y is the group —COOH and X and / or Z is n-propyl or n-butyl can be prepared analogously to the process described in U.S. Patent 3,865,755, but with in this process a bromo- (n-propyl or n-butyl) malonate instead of the halogen (methyl or ethyl) malonate and / or a sodium diethyl (n-propyl or n-butyl) tartronate instead of that in this patent Sodium diethyl (methyl or ethyl) tartronate is used.

In a further preferred embodiment of the invention, embodiment II, X is hydrogen and each radical is Y and Z, independently of the other, is hydrogen or lower alkyl, preferably hydrogen or normal alkyl. In this preferred embodiment, it is particularly preferred that the sum of the carbon atoms in Y and Z is not greater than 4 and it is particularly preferred that one of the radicals Y and Z Hydrogen and the other is hydrogen, methyl or ethyl.

The compounds of the preferred embodiment described immediately above, wherein X is hydrogen, one of the Y and Z is hydrogen and the other is hydrogen, methyl or ethyl, are used here as carboxymethoxymalonic acid, 1-

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Carboxyethoxymalonic acid or 1-carboxypropoxymalonic acid called. These three specific acids are listed below designated CMPDA, CEFDA or CPPDA for reasons of convenience. The trisodium salts of these three acids and their variations, where both Y and Z are methyl or ethyl, can by the method described in U.S. Patent 3,865,755, which patent is incorporated by reference. The trisodium salts of acids, wherein X is hydrogen and at least one of Y and Z is C ^ -C ^ -alkyl can be prepared analogously to the process described in U.S. Patent 3,865,755, in which, however, a suitably conjugated base of a lower alkyl ester of a higher alkyl substituted alpha-hydroxy acid (for example alpha-hydroxy-n-butyric acid, isovaleric acid or alpha-methyl-n-valeric acid or the like) is used instead of an alpha-hydroxy ester salt reactant provided in this patent.

In a further preferred embodiment of the invention, embodiment III, both radicals Y and Z are hydrogen

and X is the group HO - {- C -f-, where A, B and η are the

have the same meaning as above. These acids are referred to here as 2- (carboxymethoacy) -2 ^ (hydro3 [yalkyl) -malonic acids. In In this preferred embodiment, it is particularly preferred that each of the radicals A and B, independently of the other, Is hydrogen, methyl or ethyl. It is particularly preferred it is in this embodiment that when η ■ 1, at least

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one of Eeste A and B is hydrogen and the other is hydrogen, Is methyl or ethyl. In addition, it is particularly preferred in this embodiment that both radicals A and B Are hydrogen. Furthermore, it will in this embodiment it is preferred that η «1 and in the particularly preferred embodiment, that A and B are both hydrogen when η - 1.

The 2- (carboxymethoxy) -2- (hydroxyalkyl) -malonic acid, in which both A and B are hydrogen and η ■ is 1, is used as 2- (carboxymethoxy) -2- (hydroxymethyl) malonic acid (hereinafter referred to as CMHMPDA for reasons of convenience) .The trisodium salt this acid can be prepared by the method of U.S. Patent 3,897-490, cited in this publication as a whole is referred to. Other 2- (carboxymethoxy) -2- (hydroxyalkyl) malonic acids, wherein η * 1 and at least one of the radicals A and B is lower alkyl, according to Process analogous to the process of U.S. Patent 3,897 4-90 be prepared, including in this process for the formaldehyde reactant a different aldehyde (for example acetaldehyde, in which one of the radicals A and B is methyl and the other is hydrogen) or the appropriate ketone (e.g. acetone if both A and B are in the structural formula Are methyl) and in which the hydroxy radical is replaced by a suitable protective group during the ester hydrolysis stage (for example dihydropyran), which can then be removed, for example by mild acid hydrolysis. The 2- (carboxymethoxy) -2- (hydroxyalkyl) malonic acids, where η »2,

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can be prepared by the method described in U.S. Patent 3,887,616, incorporated herein by reference is taken.

In a further preferred embodiment of the invention, In embodiment IV, Y is the group -COQH and X is the group

, where A, B and η have the same meaning as

η
have up. These compounds are referred to herein as substituted oxy-bis (malonic acid) compounds. It is also particularly preferred in these embodiments that Z is hydrogen, methyl or ethyl when η ■ is 2. In particularly preferred embodiments, Z is a methyl group. In the same way, it is generally preferred in these embodiments that when η «1, at least one of the radicals A and B is hydrogen and the other is hydrogen, methyl or ethyl. It is particularly preferred in these embodiments that both radicals A and B are hydrogen.

The compound of the embodiments described immediately above, in which T is the group -COCG, I is the group HO- (CH ₂ ) - and Z is methyl, is described as 2- (hydroxyethyl) -2'-methyloxy-bis- (malonic acid) and below all reasons of expediency are designated HEMOBPDA. The tetrasodium salts of this acid and its variations when η-2 and Z is hydrogen, methyl or ethyl can be germinated by the process described in US Pat. No. 4,013,714, incorporated herein by reference. Similar salts of other acids,

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where Y -COOH, X HO-t - C -4-, η - 2 and Z low-

x B S

alkyl of at least three carbon atoms (i.e. C ^ -C ^ alkyl) can be prepared by processes analogous to the process of this patent specification, but in this process a dialkyl (C ^ -C ^ alkyl) malonate instead of a dialkyl malonate reactant, as provided in the patent is used. The epoxy reactants with two alkyl substituents on one or both carbon atoms of the epoxy ring are therefore in the process of the patent for preparation of acids of the preceding formula suitable if η β 2 and both radicals A and B in at least one

C - γ radical are alkyl, as described in US Patent B
3,887,616, incorporated herein by reference .

The tetrasodium salts of the acids, wherein Y is -COOH, X is HO- (CH ₂₎ - and Z is hydrogen, methyl or ethyl, can be prepared by the Ver to which reference is incorporated herein by drive of US Patent 3,970,698 are prepared. Similar salts of Variatio-

nen of these acids, wherein X is H0- {C J- and at least one

A and B is lower alkyl can be prepared by methods analogous to the method of U.S. Patent 3,970,698 but instead of the formaldehyde reactant, a different aldehyde (e.g. acetaldehyde, if one of the radicals A and B is methyl and the other is hydrogen) or a suitable ketone (for example acetone if both

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A and B residues in the methyl residue are used. In this process, the hydroxyl radical is shielded during the ester hydrolysis stage by a suitable protective group (e.g. dihydropyran), which can then be subsequently removed. for example by mild acid hydrolysis. Similar salts of other acids according to the preceding general formula when η «1 and Z is C 1 -C 4 alkyl can be prepared analogously to the procedure described in U.S. Patent 3,970,698, but using the appropriate diethyl (C 1 -C 4 alkyl) diglycolate instead of that in this patent provided Oiäthyldiglycolats, Diethylmethyldiglycolats or Diethylethyl diglycolate is used.

In a further preferred embodiment, embodiment V, T is a lower alkyl group and Z is

where A, B and η have the same meaning as

have up. These compounds are referred to here as 2- (carboxyal koxy) -2- (hydroxyalkyl) malonic acids. In these embodiments it is particularly preferred that when η ■ 1, at least one of the radicals A and B is hydrogen and the other is hydrogen, methyl or ethyl. Particularly preferred It is found in these embodiments that when η-1, both A and B are hydrogen. Furthermore, it is particularly preferred that η be 1 in these embodiments. It is also preferred, particularly in these embodiments, that each of T and Z, independently of the other, is lower normal alkyl, and it is particularly preferred that the sum

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of the carbon atoms in the radicals Y and Z are not greater than 4 is. Furthermore, it is preferred in these embodiments that one of the radicals Y and Z is hydrogen and the other is methyl or ethyl. In particular, in these embodiments it is preferred that one of the radicals Y and Z is hydrogen when η «is 1 and it is further preferred that one of the radicals Y and Z is methyl.

2- (Carboxyalkoxy) -2- (hydroxyalkyl) -malonic acid, in which η »1, both radicals A and B are hydrogen, one of the radicals Y and Z is hydrogen and the other is methyl, is called 2- (1-carboxyethoxy) -2 - (hydroxymethyl) malonic acid (hereinafter referred to as CEHMPDA for reasons of convenience). The trisodium salt of this acid can be prepared by the process of US Pat. No. 3,897,490, which is incorporated herein by reference. Similar salts of variations of this acid, when η »1 and in which one of the radicals Y and Z is Cp-C ^ -alkyl and / or a lower alkyl, can be prepared by processes analogous to those of US Pat. however, in this case a suitably conjugated base of a lower alkyl ester of a higher alkyl substituted alpha-hydroxy acid (for example alpha-hydroxy-n-butyric acid, -isobutyric acid, _T -isovaleric acid or the like) is used instead of one of the alpha-hydroxyester salt reactants provided in this patent. Similar salts of other 2- (carboxyalkoxy) -2- (hydroxyalkyl) -malonic acids, in which η »1 and at least one of the radicals A and B is lower alkyl, can be prepared by processes analogous to that of US Pat. No. 3,897-490, where but in this process instead of the formaldehyde reaction

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tion partner a different aldehyde (for example acetaldehyde, if one of the radicals A and B is methyl and the other hydrogen) or the appropriate ketone (for example acetone, if both radicals A and B are methyl) is used. at In this process, the hydroxy group is shielded during the ester hydrolysis stage by a suitable protective group (for example Dihydropyran), which can then be subsequently removed, for example by mild acid hydrolysis.

The trisodium salts of 2- (carboxyalkoxy) -2- (hydroxyalkyl) -malonic acids, in which η »2, one of the radicals Y and Z is methyl or Ethyl and the other is hydrogen can be prepared by the method of U.S. Patent 3,887,616 which is referred to here. Similar salts of variations of these acids when η is - 2 and either of Y and Z C, -C ^ -alkyl and / or lower alkyl can, according to processes analogous to that of U.S. Patent 3,888? 616 can be prepared, but in this case a suitable conjugated base a lower alkyl ester of a higher alkyl-substituted alpha-hydroxy acid (for example alpha-hydroxy-n-valeric acid, -isobutyric acid, -alpha-methyl-n-valeric acid or the like) is used instead of one of the alpha-hydroxy ester salt reactants provided in the patent, or it can be used in In another method described in this patent, a suitable lower alkyl ether of a higher alkyl-substituted halogen acid (for example alpha-bromo-n-valeric acid, isobutyric acid, alpha-methyln-valeric acid or the like) can be used instead of one of the halogen ester reactants provided in the patent.

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The malonic acid salts mentioned in the above embodiments I to V can be converted into the corresponding acid (for example MOBPDA, DMOPDA, CMPDA, CEPDA, CPPDA, CMHMPDA, HEMOBPDA or CEHMPDA) by treating the salt with a strong acid, for example HCl , H ₂ SO ^ or a strongly acidic ion exchange resin. Other metal salts of the acids obtained can be prepared by neutralization with the corresponding metal hydroxide, for example an alkali metal hydroxide such as potassium hydroxide. The corresponding ammonium, mono- or di- (C 1 -C, -alkyl) -ammonium- or mono- or di- (C _/ , -C- _r -alkanol) -ammonium salts can be prepared by adding such acids treated with ammonia, a suitable alkylamine or alkanolamine or hydroxide thereof by methods known to those skilled in the art.

Each of the above-described embodiments is preferred on a relatively low molecular weight basis.

In the oral preparations of this invention, the proportions in which the aforementioned malonic acid compounds are present as acids and / or partially substituted or fully substituted salts thereof are dependent on the pg value of the preparation. This p ^ value is usually between about 4 and about 11, although in some cases it can be higher or lower than this range. Below about p "4 there is a greater risk of damage to the tooth enamel in spite of the relative safety of the aforementioned acid or its salts. Above about 11 p _H greater difficulties arise with regard to a satisfactory taste in formulating the products

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and milder effect. A preferred Pg range is between about 6 and about 10. In many embodiments, are the physiologically compatible salts used, preferably water-soluble salts, such as, for example, sodium, potassium or ammonium salts, in order to facilitate their dissolution in the saliva.

Some embodiments of this invention are oral hygiene products such as dentifrices, mouthwashes, fasting for prophylaxis and topical solutions. A dentifrice, particularly toothpastes, containing a tartar-inhibiting amount of an acid of the preceding general formula and / or contain a physiologically acceptable salt thereof is a preferred embodiment of the invention. A mouthwash containing such an acid and / or a salt thereof is a further preferred embodiment. In addition to the forms of application of a malonic acid compound described here, many formulations of such products are known to the person skilled in the art. For example, typical formulations of toothpastes and mouthwashes made with the tartar-inhibiting compounds are of the type described here Invention in U.S. Patents 3,639,569, 3,544,678, 3,678,154, and 3,959,458 described, to which reference is made here in its entirety.

Under conditions of normal use, the oral preparations of this invention are physiologically acceptable, i.e., for Suitable for introduction into the oral cavity without any discernible adverse effect on the tooth structure or other health

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damage to health. Within the limits of such physiological ability, the tartar-inhibiting amounts and concentrations of the aforementioned malonic acid compounds can vary widely in the oral preparations of this invention. Such amounts and concentrations can easily be determined for any type of oral preparation by the person skilled in the art. In general, concentrations from 0.01 to about 10 # are preferred. Oral preparations which, in normal use, are incidental or intended for digestion, may contain relatively small amounts, but still contain highly effective concentrations. Of course, such a preparation supplied for digestion should be physiologically (ie digestive) tolerable. Accordingly, a mouthwash of this invention typically contains between about 0.1 and about 3 # of the aforementioned tartar-inhibiting compound. Teeth cleaning preparations, optical solutions and prophylactic pastes, the latter normally being prescribed by a doctor, may desirably contain up to about 10 # or even more of the calculus-inhibiting compounds, but usually contain between about 0.1 and about 5 #, and especially between about 1 and about 2%.

Although it is not intended to limit the invention to any theory of operation, it has been observed, that the aforementioned malonic acid compounds inhibit tartar formation by converting the solute Calcium phosphate in the saliva to prevent crystalline deposits in the manner of calcium hydroxyapatite. It included

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therefore the preparations of this invention preferably insoluble polyvalent cations in an amount such that the The crystal growth-inhibiting ability of the compounds is depleted to such an extent that their tartar formation-inhibiting Effectiveness would thereby be essentially neutralized.

The specific examples below are for the purpose only the explanation without restricting the scope of the invention.

Examples 1 to 9

A. Tartar Inhibition Ratings

Evaluations of the effectiveness of the compounds used in this invention in inhibiting tartar formation were made essentially in the manner described in "A Method and Apparatus for Studying In Vitro Calculus" by S. Yankelowitz et al of Colgate-Palmolive Co., Journal of Dental Research 44 (No. 4), 648-53 (1965). According to this method, which is known to those skilled in the art, the simulated oral tartar deposits intended to form are caused by mechanically rotating slides sideways and vertically at 0.5 rpm in such a manner that each slide alternates through a small sample of intact human Saliva containing 0.1% added monocalcium phosphate is passed and then exposed to a stream of air which at least partially dries each slide before it is again passed through the saliva sample . It was found that, as this so-

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just stated in the cited article, the tartar deposits obtained in both oral tartar deposits similar in composition and in the X-ray diffraction pattern are.

For the present evaluations, 150 ml of simulated ones are collected Saliva for three days (50 ml / day) from a donor whose saliva is very prone to tartar formation. The saliva collected is still of such a nature that under the experimental conditions the formation of tartar due to AHDP is essential is more strongly inhibited than by water, which is used instead of ÄHDP in a comparative experiment. Every portion of saliva of 50 ml is kept frozen until used. At this point the mixed 150 ml is neutralized Sample on p ™ 7 +. 0.05 after adding 0.1 # monocalcium phosphate, then stir thoroughly and divide the sample into 25 ml portions.

1 ml of a 0.1 M solution of the trisodium salt of CMPDA, CEPDA, CPPDA, CEHMPDA or CMHMPDA or the tetrasodium salt * of HEMOBPDA, MOBPDA or DMOBPDA are added to one portion. A second part is given 1 ml of a 0.1 M solution of an agent according to the state of the art, the anti-tartar compound ÄHDP. Each of the solutions that are added to these portions are neutralized beforehand with NaOH or H ₂ SO ^. Add 1 ml of distilled water to a third portion.

For comparison purposes, the three test samples are then placed in the same side-by-side containers in an oven. The-

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ser is equipped with a device that allows a separate set of three 22 χ 40 cm glass slides (those in at an angle of approximately 120 ° to each other in relation to the rotating shaft on which they are mounted) is rotated through each of the saliva containers with a steady horizontal stream of air directed against the slides and perpendicular to the axis of their rotation. All slides used are essentially the same and so on Shaft attached so that an equal portion (24 mm) of the length of each slide is passed through the appropriate saliva sample.

In the heating furnace described above, the tartar formation study is carried out in 20 successive stages, with the inside of the furnace at 37 +. 1 ⁰ C and with a relative humidity between 76 and 78 $. The saliva samples are then removed from the oven and the slides rotated in the air stream for an additional hour before removing them from the heating oven. The weight of each slide and a deposit remaining on it is then compared with the weight of the slide before it is used in the investigation and visual assessments of the deposits are made, for which purpose photographs are taken of each object under the same conditions, in order to avoid further inaccuracies off in these ratings. The results are recorded separately for each of the three slides in each set and then averaged. The entire procedure is then repeated using saliva from another donor. With some of the for evaluation

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intended malonic acid compounds were further comparative studies using saliva of the same Donor or using saliva from another donor. The results of the various investigations are averaged in each case, giving the results given here.

1. MOBFDA

During the investigations of the tetrasodium salt from MOBPLA found that the weights of the simulated tartar on the slides corresponded to the saliva containing the salt were exposed averaged 0.37 mg, with the Deposits on the microscope slides used in comparative tests with ÄHDP averaged 0.4-8 mg and in comparative tests with water averaged 0.93 ng. It was therefore used in the trials of the tetrasodium salt of MOBPDA, the formation of the simulated tartar was on average 23 # less than in the comparative tests when using ÄHDP and 6o # less than in comparative tests using water. In the visual observations, the amounts were opaque Material deposited on slides exposed to saliva contained in the tetrasodium salt of MOBPDA were, on average, in the range of 0 to 25 on an im essentially linear rating, where 100 represents the amount of opaque material on the slides occurs in comparative examinations with water and O is the amount of such a material on microscope slides that in comparative examinations can be used with ÄHDP.

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- .22 -

2. DMOBPDA

During the investigation of the tetrasodium salt of DMOBPDA was found that the weights of simulated tartar on the slides corresponded to the different types of saliva that made the salt contained, were exposed, averaged 0.45 mg, with comparative bookings on the slides Using AHDP an average of 0.42 mg and using water an average of 0.98 mg were deposited. The experiments therefore show that when using the tetrasodium salt by DMOBPDA, simulated tartar formation is on average $ 54 less than comparative studies with Water, while in comparative studies using ÄHDP the results are on average $ 57 less than the use of water · In the visual assessment The amounts of opaque material deposited on the slides were that of the tetrasodium salt of DMOBPDA-containing saliva types were exposed, on average essentially the same as the slides that were used in comparative studies with AHDP and around the Half less than all on microscope slides that were used in comparative tests with water.

3. CMPDA

During the investigation of the trisodium salt of CMPDA was found that the weights of simulated tartar on the slides exposed to saliva produced the Salt averaged 1.00 mg, while in comparative studies the slides in use

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of ÄHDP averaged 0.62 mg and, when using water, averaged 1.48 mg. In the tests using the salt of CMPDA, the formation of simulated tartar was on average 32 # less than in comparative tests when using water, while in the comparative tests when using ÄHDP it was 58 # less than in comparative tests with water. In the visual assessment, the amounts of opaque material on the slides exposed to the saliva containing the sodium salt of CMPDA were rated as being below 33 on average when rated on an essentially linear scale with 100 being the amount of opaque material on the slide when using water and O represents the amount of such material on the slide when using ÄHDP. Furthermore, in visual evaluations, the amounts of opaque material deposited on the slides were rated as being less than half the average of the amount on the slides used in comparative tests with water.

4. CPPDA

Tests of the trisodium salt of CPPDA found that the weights of simulated tartar on slides exposed to the saliva containing the salt averaged 0.34 mg, while comparative tests averaged the slides using AHDP 0.27 ng and when using water the average was 0.55 mg. It was therefore with the

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Trying to use the salt of CPPDA the formation of simulated tartar averaged $ 38 less than at Comparative experiments with water, while comparative experiments with ÄHDP were on average $ 51 less than in comparison tests with water. In the visual assessment, the amounts of opaque material on the slides exposed to the types of saliva containing the CPPDA salt were rated as being on average substantially below 25 on a scale of 0 to 100, as described in the previous example, and that they were less than half the size of the deposits the slides for comparative tests with water.

5. CEPDA

During the investigations of the trisodium salt of CEPDA was found that the weights of simulated tartar on the slides that were exposed to the saliva species that contained the salt, averaged 0.83 ng, while in comparative studies the slides using ÄHDP averaged 0.17 mg and in experiments with water averaged 0.60 mg. Therefore, in the experiments using salt from CEPDA, the weight of the deposits was on average $ 38 greater than that of Comparative examinations with water, while in comparative examinations with the use of IHDP they averaged around $ 72 less than the water trials. The visual assessment measured the amount of opaque material on the slides that was related to the types of saliva that contained the

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CEPDA-SaIz contained, classified so that they were on average were no higher than 25 on the scale from 0 to 100, as before and that they were less than half the size of the deposits on the slides in comparative tests with water.

6. CEHMPDA

In these investigations it was found that the weights of simulated tartar on the microscope slides containing the types of saliva which contained the trisodium salt of CEHMPDA averaged 0.58 mg, during the comparative tests the slides when using ÄHDP an average of 0.44 mg and the slides for comparative examinations with water averaged 0.83 mg. It was therefore in the experiments using the trisodium salt from CEHMPDA, the formation of simulated tartar was on average 3O # less than in comparative tests with Water, while in the comparative experiments using ÄHDP they were on average 47 # lower than in Comparative tests with water. In the visual assessment, the amounts of opaque material on the slides, those who were exposed to the types of saliva with the trisodium salt of CEHMPDA were classified in such a way that they were not higher than 33 and on average below 25 when assessed according to the im essential linear scale from 0 to 100, as described above. Furthermore, the visual ratings the amounts of opaque material deposited on the slides are classified as im

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significantly less than half as large as the amount on the slides that were obtained in comparative tests on the slides with water.

7. HEMOBPDA

In these investigations it was found that the weights simulated tartar on the slides exposed to the types of saliva containing the tetrasodium salt of HEMOBPDA averaged 0.38 mg, while comparative studies used the slides of ÄHDP on average 0.55 mg and when using water averaged 0.87 mg. It was therefore in the experiments using the tetrasodium salt of HEMOBPDA Simulated tartar formation averaged $ 31 less than the comparative tests using ÄHDP and $ 56 less than comparative exams at Use of water. The visual assessment was the amount of opaque material on the slides that were exposed to saliva containing the tetrasodium salt of HEMOBPDA, rated as being on average were essentially the same as the slides used in the comparative tests ait ÄHDP and less than half as large as the deposits on the slides as in the comparison tests with water.

8. GMHMPDA

During the investigation it was found that the weights at simulated tartar on the slides that hold the saliva

809818/0985

species were exposed to the trisodium salt of CMHMPDA contained, averaged 0.17 mg, while in comparative examinations the slides when using ÄHDP on average 0.28 mg and when using water on average 0.85 mg. It was therefore with the experiments Using the trisodium salt of DMHMPDA, the formation of simulated tartar is on average 39 # less than with the comparative tests when using ÄHDP and 80 # less than the comparative tests when using of water. The visual assessment measured the amount of opaque material deposited on the slides those exposed to the types of saliva containing the trisodium salt of GMHMPDA were rated as being in the range from 0 to 25 on the scale from 0 to 100, as above described, lay.

B. Manufacture of oral preparations

The compounds examined in Part A of these examples, the corresponding acids and other physiologically compatible ones Salts of these acids are useful for inhibiting tartar formation when in acceptable carriers or pharmaceuticals Vehicles of the usual type are introduced. Examples follow for mouthwash preparations that contain at least one of these compounds.

809818/0985

Examples

Components glycerin Ethyl alcohol water 809 8 Tween 80 ¹
Saccharin »Ft
OO Natriuecyclaaat S860 / Flavor
Fully substituted
Salt from CEHMPDA,
CMFDA, CEFDA or
• CFPDA

Fully substituted salt from MOBPDA, DMOBPDA, CMHMPDA or HEMOBPDA

JL _2_ JL

4 5 6

Parts by weight

JL

10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0

16.5 16.5 16.5 16.5 16.5 16.5 16.5 16.5

67.172 67.172 67.172 70.192 67.172 67.172 67.172 70.192

0.12 0.12 0.12 0.12 0.12 0.12 0.12 0.12

0.045 0.045 0.045 0.02 0.045 0.045 0.045 0.02

0.75 0.75 0.75 0.04 0.75 0.75 0.75 0.04

0.088 0.088 0.088 0.088 0.088 0.088 0.088 0.088

^: 5.0

7.0

'4.0

7.0

8.5 10.0

'3.0
7.0

'4.0
8.0

'2.0 9.0

10.0

¹ polyoxyethylene (20 mol ethylene oxide) sorbitan monooleate a non-ionic emulsifier from Atlas Powder Co.

Ammonium salt
* Triethanolammonium salt

Sodium salt
^ Potassium salt

Ammonium salt

'Potassium salt

Triethanolammonium salt

⁷ triethylammonium salt

Adjusted to this value with sodium hydroxide or

Sulfuric acid.

The following is an example of a toothpaste containing at least one of these compounds.

Water 31.58

Sorbital 6.25

Saccharin 0.12

Calcium pyrophosphate 39.00

Glycerine 18.00

Sodium alkyl (coconut) sulfate 0.40

Sodium Coconut Monoglyceride Sulphonate 0.75

Sodium carboxymethyl cellulose 1.15 Magnesium aluminum part 0.40

Taste t offe O 85

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MOBPDA, DMOBPDA, CMHMPDA, HEMQBPDA,

CEHMPDA, CMPDA, CEPDA or CPPDA 1.00

ph ^{2 5> 9} °

¹ Manufactured according to U.S. Patent 3,112,247

² Adjusted to the specified pg value with sodium hydroxide.

Other examples of toothpastes which contain at least one of the aforementioned malonic acid compounds correspond essentially the previous toothpaste preparation, except that the corresponding potassium or ammonium salt is the Malonic acid compound in Example 9 was used.

Other examples of oral preparations comprising at least one of the compounds include other mouthwashes and toothpastes, tooth powders, toothpastes and pastes for prophylaxis that the dentist or dental technician uses to polish the Teeth used after removing the limestone. Examples of such preparations except that they are tartar-inhibiting Contain compound according to the present invention, are in U.S. Patents 3,544,678, 3,639,569,

3,678,154 and 3,959,568. Typically they are toothpastes aqueous preparations containing a polishing agent, a surfactant, a binder, solvent, preservative, Contain flavorings and optionally therapeutic agents. Mouthwashes typically contain water, ethanol, Flavors, colors and optionally a surfactant. For further examples of oral preparations that at least containing any of the compounds of this invention

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human food such as sodas, confectionery, pastries, etc., pet food or living inventory, chewing gum, etc. Chewing gum typically contains base materials, plasticizers, Sugar or other suitable carbohydrates such as glucose, sorbitol, etc. Sugarless chewing gum can contain other sweeteners such as Contain saccharin or sodium cyclamate. The ingredients of each of the aforementioned oral preparations, except for previously mentioned malonic acid compounds, as well as various mixtures these ingredients are typical of carriers useful in the oral cavity of the present invention.

In summary, the present invention relates to oral preparations, such as mouthwashes, toothpastes, foods, chewing gum and the like that contain certain propanedioic acid (malonic acid) compounds to inhibit tartar formation.

'' * ' -Patent claims-

8098 1 8/0985

Claims (15)

Patent claims: 1. Oral preparation for inhibiting tartar formation, characterized in that it comprises (1) a substituted malonic acid compound of the general formula COOH COOH X-C-O-C-Z, I t COOH Y Y is -H, -COCH and / or lower alkyl with the proviso that Y is -COOH when X is lower normal alkyl and Y is not Is -COOH when X is -H, Z is -H and / or lower alkyl with the proviso that Z is -H or lower normal alkyl when X is lower normal alkyl A and B, independently of one another, -H and / or lower alkyl are, η = 1 or 2, and the physiologically acceptable salts of these acids (2) a carrier suitable for use in the oral cavity, the compound in the preparation being sufficient The amount and concentration is present to substantially inhibit tartar formation. 2. Preparation according to claim 1, characterized 809818/0985 ORIGINAL INSPECTED indicates that the carrier is a dental polish, flavor, chewing gum base or human or animal food is. 3. Toothpaste according to claim 2. 4 ·. Mouthwash according to claim 2. 5. Oral hygiene preparation according to claim 2. 6. chewing gum according to claim 2. 7 · Food according to claim 2 for digestion by humans or animal. 8. Preparation according to claim 2, characterized in that the malonic acid compound Is methyloxy bis (malonic acid). 9. Preparation according to claim 2, characterized in that the malonic acid compound Is dimethyloxy bis (malonic acid). 10. Preparation according to claim 2, characterized in that the malonic acid compound Is 2- (carboxymethoxy) -2- (hydroxymethyl) malonic acid. 11. Preparation according to claim 2, characterized in that the malonic acid compound 809818 / 098S 27A957Q Is carboxymethoxymalonic acid. 12. Preparation according to claim 2, characterized that the malonic acid compound is 1-carboxyethoxymalonic acid. 13. Preparation according to claim 2, characterized in that the malonic acid compound 1-carboxypropoxymalonic acid is. 14. Preparation according to claim 2, characterized that the malonic acid compound is 2- (hydroxyethyl) -2'-methyloxy-bis (malonic acid). 15. Preparation according to claim 2, characterized that the malonic acid compound is 2- (1-carboxyethoxy) -2- (hydroxymethyl) malonic acid. 809818/0985