DK162419B - ORAL COSMETICS THAT EFFECTS THE TURTLE - Google Patents

Description

DK 162419 B

The invention relates to oral care agents containing an anti-tooth stone agent.

Tartar is a hard mineralized formation that forms on the 5 teeth. Regular brushing prevents rapid build-up of these deposits, but even regular brushing is not enough to remove all the tartar that is deposited and which sticks to the teeth. Tartar is formed on the teeth as calcium phosphate crystals begin to deposit in the retina and the extracellular matrix of dental plaque becomes tightly packed enough to make the aggregates resistant to deformation. There is no complete consensus on the path by which calcium and orthophosphate eventually become the crystalline material called hydroxy-apatite (HAP). However, there is a general consensus that at higher saturations, i.e. Above the critical saturation limit, the precursor to crystalline hydroxyapatite is an amorphous or microcrystalline calcium phosphate. "Amorphous calcium phosphate" is similar to hydroxyapatite, but differs therefrom in its atomic structure, particle morphology and stoichiometry. X-ray diffraction patterns of amorphous calcium phosphate show broad peaks typical of amorphous materials lacking the long-range atomic order characteristic of all crystalline materials, including hydroxyapatite. A proposed mechanism by which the non-toxic anti-tartar agents of the invention inhibit tartar formation probably implies that these agents act to bind amino groups in the oral cavity system at a physiological pH and physiological temperatures and also cross-link the protein. .

A considerable number of different types of compounds and agents have been developed for use as antibacterial agents, anti-plaque agents, and anti-dentifrice agents in oral care products, including e.g. such cationic materials as the bis-biguanide compounds and quaternary ammonium compounds, e.g. benzethonium chloride and cetylpyridinium chloride. These cationic mates

DK 162419 B

However, 2 rials are prone to discoloring the teeth when continued use.

According to U.S. Patent No. 4,080,441, it is proposed to inhibit the above discoloration caused by the cationic antibacterial anti-stick agents by adding to the mouthpiece as an anti-stain additive a compound for which it has now been found to be more fully described hereinafter. in itself acts as an effective oral anti-tartaric agent in the absence of the cationic antibacterial anti-lacquer agents.

The object of the invention is to provide an improved oral care agent which counteracts tartar which has relatively small or no tendency to discolor teeth.

BACKGROUND OF THE INVENTION This invention relates to a substantially anhydrous oral care agent which is free of discolouring antibacterial antibacterial agents and comprises an orally acceptable carrier, and in an effective amount as anti-tartaric agent, at least one bis (o-carboxyphenyl) ester of a C2-C8. aliphatic dicarboxylic acid.

The anti-tartar agents of the invention may be represented in their free acid form by formula 25

OOC - (CRR1 - COO

1 n λ

-COOH HOOC

Wherein preferably the R's are independently H or C 1-4 alkyl, preferably H, and n is a number from 0-6, preferably 2, the preferred anti-tartar agent being bis- (o-carboxy-phenyl) succinate ( BOCS). However, the group - (CRR) n - may be a narrow bond when n is 0 as in the bis ester of oxalic acid, or may be any C 1-6 alkylene or alkenylene group, ie. just-

DK 162419 B

3 chained or branched, saturated or unsaturated interrupted in the chain of 0 or S, C 1-4 a 1 -koxy substituted or the like. When the --CRR group is part of an ethylenic group, one or both R may be 0, i.e. is replaced by a valence bond. The bis (o-5 carboxyphenyl) esters of the following aliphatic dicarboxylic acids are intended to illustrate only the anti-tartaric agents of the invention: oxalic acid (ethanedioic acid malonic acid (propanedioic acid) (butanedioic acid glutaric acid (pentanedioic acid) , 2-ethylenedicarboxylic acid HOOCCH; CH-COOH) itaconic acid (methylene succinic acid HOOCC (JCE ^) CH CH: CHCOOH) 2o dihydroitaconic acid (methyl succinic acid) 3-ethylhexanedioic acid

Furthermore, one or both of the phenyl moieties of this agent may be nucleosubstituted with one or more G 1 alkyl or alkoxy groups, such as methyl or isobutoxy, or halogen, such as chlorine, bromine, iodine or fluorine.

Suitable methods for preparing these anti-tartar agents are described in the aforementioned U.S. Patent No. 4,080,441. Another improved method of this preparation is described in the following Example A.

It will be appreciated that the free acid form of these antitanking agents may be converted to and used in their equivalent salt form by treatment with a base containing an orally acceptable table cation such as alkali metal (e.g. sodium, potassium), alkaline earth metal (e.g., calcium, magnesium), metal, ammonium, mono-,

DK 162419 B

4 di- or tri-C 1-8 alkyl or alkanol-substituted ammonium or organic amine (e.g., methyl, ethyl, hydroxyethylene substituents).

The dentifrice antifouling agents of the invention are anticorrosive agents, and are effective in reducing tartar formation without unnecessary descaling of the dental enamel, and, unlike the above cationic, antibacterial antifouling agents and antifouling agents, these agents have no or little tendency to discolor teeth and may further prove effective in reducing or inhibiting gingivitis.

The concentration of these antifungal agents in oral care products can vary greatly, typically upwards from approx. 0.01% by weight without an upper limit on the amount that can be used, except in so far as it is determined by cost and incompatibility with the carrier. Generally, concentrations from about 0.01% to approx. 10%, preferably approx. 0.05% to approx. 8.0% and best approx. 0.1% to approx. 4% by weight. Oral care products which could be mistakenly taken into use during normal use contain incremental concentrations in the lower portion of the aforementioned ranges.

Although these antitanking agents vary in water solubility 25 depending on their molecular weight, identity and amounts of salt forming cations, etc., they are sufficiently soluble in aqueous media, e.g. in the oral cavity, in the low concentrations used herein to be called water-soluble. However, it has unexpectedly been found that oral care agents containing these agents in an aqueous medium undergo considerable hydrolysis or other deterioration upon storage. According to the invention, oral agents which are substantially anhydrous, e.g. contains 0 to less than approx. 0.2 moles of water per mole of antitank stoning.

When the oral agents of the invention are in liquid, paste or cream form, such as in mouthwashes and rinse fluids,

DK 162419 B

For example, in toothpastes and toothpastes, a water-miscible (preferably water-soluble) organic normally liquid, orally acceptable carrier is used. Typically, these carriers include water-soluble C 2-4 monovalent and polyhydric alkanes and C 1-4 alkyl ethers thereof, such as ethanol, ethylene glycol, methyl, ethyl and butyl ethers thereof (methyl, ethyl and butyl-Cello-solv®), propylene glycol, tetramethylene glycol and glycerine and water-soluble polyethylene glycols) such as diethylene glycol, methyl, ethyl, diethyl and butyl ethers thereof (methyl, ethyl, diethyl and butyl Carbitol), triethylene glycol, low molecular weight polyethylene glycols, e.g. 400, 600 and mixtures thereof, etc. The polyhydroxy compound in the aforementioned group, especially propylene glycol, glycerine and the low molecular weight polyethylene glycols, generally acts as moisture binding agents which are desirable components of the oral care compositions of the invention.

Other types of these water miscible liquid carriers which may be used are the polar aprotic solvents such as dimethyl formamide and sulfoxide, N-methylpyrrolidone, sulfolane, tetramethylsulfone, acetonitrile and preferably ethylene and propylene carbonate.

Organic liquid carriers which are substantially miscible with water may also be used, and representatives thereof are hydrocarbon, fatty and fatty acid esters such as mineral oil, tetradecane, pentane, capric acid, oanoic acid, methylcaproate and laurate, ethylene glycol dicaprylate and the like.

Of course, mixtures of the same types and / or different types of liquid carriers as described above can be used.

The amount of the aforementioned liquid carrier used in these mouthpieces will, of course, depend for most of the desired degree of fluidity or viscosity and can be readily determined routinely in a given case. Typically, liquid agents such as mouthwashes and rinse fluids contain approx. 70¾

DK 162419 B

6 to approx. 99.9%, and toothpastes and toothpastes contain approx. 10% to approx. 80% by weight of such a liquid carrier, of which approx. 10% to approx. 100% can be a moisture-binding agent. Normally solid moisture binding agents such as sorbit may also be included.

5

The mouthwash agents of the invention typically have in aqueous medium, e.g. in the oral cavity, or in the form of a 20% aqueous slurry or solution, a pH value of approx. 3.5 to approx. 8, preferably approx. 4 to approx. 7 and best approx. This pH-10 value can be adjusted by adding the necessary amounts of acidic substances such as citric or benzoic acid, basic substances such as sodium hydroxide and / or buffers such as sodium citrate, benzoate, bicarbonate or carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate or mixtures thereof.

The carrier in solid or paste-like agents, such as tooth powders, tablets, toothpastes and toothpastes, usually contains powder material. Examples of polishing materials are water-insoluble sodium metaphhopate (IMP), calcium metaphosphate, tricalcium phosphate, anhydrous monohydrate in serous and dihydrated calcium and dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnium and calcium phosphate, magnesium and calcium. sulphate, alumina, hydrated alumina, aluminosilicate, alkali metal and alkaline earth metal aluminosilicates, zirconium silicate, silica, bentonite and mixtures thereof. Preferred polishes include crystalline and colloidal silica, silica gel, complex, amorphous alkali metal aluminum silicate, hydrated alumina and IMP.

30

Alumina, in particular the hydrated alumina hydrate marketed by Alcoa as C333, having an alumina content of 64.9% by weight, a silica content of 0.008%, a ferric oxide content of 0.003% and a moisture content of 0.37% at 110 ° C, 35 and having a density of 2.42 and a particle size such that 100% of the particles are less than 50 microns and 84% of the particles are less than 20 microns, is very effective.

DK 162419 B

7 When visually clear gels are used, a colloidal silicon dioxide polish such as those sold under the trademark SYLOID® as Syloid 72 74 or 244 or under the trademark SANTOCEL ™ (not reg.) As Santocel 100, and alkali metal aluminum silicate complexes are particularly useful since they have refractive index close to the refractive index of the gelling and liquid systems commonly used in dentifrices.

Many of the so-called water-insoluble polishing materials are of anionic nature and also contain small amounts of soluble material. Thus, insoluble sodium metaphosphate may be formed in any suitable manner as illustrated by Thorpes Dictionary of Applied Chemistry, Volume 9, 4th Edition, pages 510-511. The forms of insoluble sodium trimetaphosphate known as the salt of Ma- drell and Kurrol's salt are other examples of suitable materials. These metaphosphates exhibit very little solubility in water and are therefore generally referred to as insoluble metaphosphates. There is a smaller amount of soluble phosphate material as impurities, usually a few percent, such as up to 4% by weight. The amount of soluble phosphate material which is believed to include a soluble sodium trimetaphosphate in the case of insoluble metaphosphate can be reduced by washing with water if desired. The soluble alkaline imetimethaphosphate is typically used in powder form with a particle size such that no more than 1% of the material is greater than about 10%. 37 microns.

The polishing material is generally found in amounts ranging from approx. 20% to approx. 99% by weight of the oral care product. Preferably, it is found in amounts ranging from about 20% to about 75% in toothpaste and from approx. 70% to approx. 99% in tooth powder.

In the manufacture of dental powders, it is usually sufficient mechanical to mix, e.g. by grinding, the various solid components in appropriate amounts and particle sizes.

In a toothpaste cream or gel, the amounts of liquids and solids are typically adjusted to form a creamy or gel-like.

DK 16 2 419 B

fairly mass, which can be squeezed from a pressure vessel or by a compressible tube. Thickening to the desired viscosity or flowability is typically facilitated or achieved by including a binder, thickener or gelling agent such as natural or synthetic gums or gum materials, typically Irish moss, Pluronic®, sodium carboxymethyl cellulose and carboxyethyl cellulose, methyl cellulose , hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, Laponite® CP or 10 SP (synthetic hectoritles from Laporte Industries Ltd.), viscarin, gelatin, glucose, sucrose, Carbopol® (eg 934, 9 and 941), karaya rubber. gum arabic, rag-an t, polyvinylpyrrolidone, polyvinyl alcohol and starch. They are usually found individually or several together in an amount up to approx. 10 weight percent, preferably in the range of about 0.5% to approx. 5%. The preferred gelling agents are PLURONICs and hydroxypropyl cellulose. PLURONICs such as F108 and F127 are polyoxypropylene polyoxyethylene block polymers which simultaneously act as nonionic surfactants.

20

The oral care compositions of the invention may contain a non-sealable synthetic sufficiently water-soluble, organic, anionic or nonionic surfactant at concentrations generally ranging from about 1 to about 5%. 0.05 to approx. 10, 25 preferably approx. 0.5 to approx. 5% by weight, to promote wetting and cleansing and foaming properties. For suitable anionic surfactants and suitable nonionic surfactants, see U.S. Patent No. 4,041,149.

In certain embodiments of the invention, a fluorine-given compound is present in the oral care agent. These compounds may be slightly water-soluble or completely water-soluble. They are characterized by their ability to release fluorine ions in water and by being essentially free of reaction 35 with other compounds in the oral care agent. Among these materials are inorganic fluorides such as soluble alkali metal, alkaline earth metal and heavy metal salts, e.g. sodium fluoride,

DK 162419 B

9 to 9 fluoride, ammonium fluoride, calcium fluoride, a copper fluoride, such as copper fluoride, zinc fluoride, a tin fluoride, such as stannous trifluoride or stannous chlorofluoride, barium fluoride, sodium fluoride, sodium sulfate, ammonium fluoride, Alkali metal and tin fluorides such as sodium and stannofluoride, sodium monofluorophosphate and mixtures thereof are preferred.

The amount of the fluorine-providing compound depends to some extent on the type of compound, its solubility and the type of oral care agent, but must be a non-toxic amount. In a thickened or solid oral care agent, such as toothpaste or tooth powder, an amount of such a compound which releases a maximum of approx. 1% by weight of the preparation, too satisfactory. Any suitable minimal amount of such a compound may be used, but it is preferred to use sufficient compound to release approx. 0.005% to 1% and preferably approx. 0.1% fluoride ion. Typically, in the case of alkali metal fluorides and stannofluoride, this component is found in up to about 10%. 2% by weight based on the weight of the composition and preferably in the range of about 0.05 to 1%. In the case of sodium monofilorphosphate, the compound can be found in an amount up to 7.6% by weight, more typically approx. 0.5 to approx. 1% by weight.

In a liquid oral care agent, such as a mouthwash liquid, the fluorine-providing compound is typically present in an amount sufficient to release up to approx. 0.005 to approx. 0.2%, preferably approx. 0.001 to approx. 0.1% and best approx. 0.0013 wt% fluoride ion.

Various other materials can be incorporated into the mouth care agents of the invention, such as whitening agents, preservatives, silicones, chlorophyll compounds, other anti-tartar agents, antibacterial anti-plaque agents and / or ammoniated materials such as urea, diammonium phosphate and mixtures thereof. When these additions are present, incorporate

. DK 162419 B

10, they are porated in the compositions in amounts which have no significant detrimental effect on the desired properties.

Any suitable flavoring or sweetening material may also be used.

Examples of suitable aromatizing ingredients are aromatic oils, e.g. garden mint, peppermint, winter green, sassafras, spice ike, sage, eucalyptus, marjoram, 10 cinnamon, lemon and orange, menthol, eugenol, cineol and methyl salicylate. Suitable sweeteners include sucrose, fructose, lactose, maltose, sorbit, xylite, sodium cyclamate perillartin, APM (aspartylphenylalanine methyl ester) and saccharin. Conveniently, the aroma and sweetener may together amount to approx. 0.01 to 5% or more of the composition.

In the preparation of the oral care compositions of the invention, it is preferred, but not essential, to add the antitanking agent after the other ingredients are mixed and brought into contact with each other to avoid a tendency for this agent to precipitate.

It will be understood that the oral care products must be sold in the usual manner or otherwise distributed in suitably labeled packages. Thus, a glass with a mouthwash 11 liquid will have a label describing it as a mouthwash 1 liquid or mouthwash liquid and containing instructions for use, and a toothpaste will usually be in a compressible tube, typically aluminum, lined lead or plastic, or a another compressible pack for measuring the contents having a label describing it as a toothpaste or toothpaste.

In carrying out the invention, a mouthwash agent according to the invention, such as a mouthwash liquid or toothpaste, containing the described anti-toothpaste agent in an amount effective to prevent tartar on tooth surfaces is used regularly in the oral cavity, especially on the tooth enamel, preferably from 1-3 times daily. .

11

DK 162419 B

Example A

Preparation of bis (o-carboxyphenyl) succinate 0.4 mol of salicylic acid (55.2 g) 0.4 mol of pyridine (31.2 mil 0.2 mol of succinyl chloride (31.0 g).

The salicylic acid and pyridine are dissolved in 90 ml of acetone. To the resulting clear solution, the succinyl chloride is added to 90 ml of acetone with stirring at a rate which keeps the acetone under reflux for 1 hour. During this addition, the desired BOCS product begins to separate and the mixture turns dark purple. The reaction slurry is stirred for 1 hour after all the succinyl chloride has been added. Then 200 ml of water is added, the acetone is evaporated from the slurry on a rotary evaporator at 35 ° C and the desired BOCS product is collected on a suction filter, washed with water and dried in vacuo at 60 ° C.

20

Yield 66.5 g (93%)

Mp. 177 to 177.5 ° C

Neutral Ices in Equivalent 179.9 *

Saponification equivalent 186.8 * 25 * Calculated for C

The following examples further illustrate the nature of the present invention. All amounts discussed below are by weight and temperatures in ° C, unless otherwise stated.

30

Example 1 The following composition illustrates a toothpaste according to the invention that is effective in preventing tartar.

35 5

. DK 162419 B

12 Weight Parts

Propylene glycol 42.0

Hydroxypropyl cellulose 1.0

Polyethylene Glycol 60Q 10.0

Sodium saccharin 0.2

TiO2 0.4 IMP 28.0

Syloid 244 12.0

Sodium lauryl sulfate 1.5

Aroma 1, o 'BOCS 3.0

The following compositions listed in parts by weight illustrate mouthwash fluids of the invention which are effective in preventing tartar.

Example 2 ..... 3 4 Flavor, 0.22 0.22 0.22

Ethanol 15.0 15.0 15.0

Pluronic F108 3.0 3.0 3.0

Glycerin 1Q, 0 10.0 10.0

Sodium saccharin Q, 0.03 0.03 0.03 25 BOCS ° rQ5 ° '50 1' °

The mouthwashes of Examples 2-4 above can be used in the oral cavity as they are or after dilution by ca. 2-4 times their volume of water, ie. volume ratio of preparation to water 30 of approx. 1: 2 to approx. 1: 4.

Use of equivalent amounts of the following bisester-containing compounds instead of BOCS used in the compositions of Examples 2-5 gives compositions which are also effective in preventing tartar.

13

DK 162419 B

Example Bis-ester-containing compound 5 bis (2-carboxy-4-butoxyphenyl) oxalate 6 bis (2-carboxyl-4-propyl-6-chlorophenyl) glutarate 7 bis (2-carboxy-4-methyl-6-bromophenyl) adipate 5 8 bis (2-carboxy-4-iodo-6-ethoxyphenyl) suberated 9 bis (2- carboxyphenyl pimelate 10 bis (2-carboxy-5-methoxyphenyl) malonate 11 bis (2i-carboxy-6-butylphenyl) maleate 12 bis (2-carboxyphenyl lithaconate 13 bis (2-carboxy-4-fluorophenyl) muconate

Example 14

In this study in 24 rats, a placebo of water and 15 a 0.1¾ solution of BOCS in di methylsulfoxy d, pH 7.10, was evaluated as experimental antitumor rinse fluid for efficacy against tartar formation for a period of 30 days.

Osborne-Mendel rats used in litters are used.

On days 21 and 22, they were grafted intraorally with Strepmutans and Acti-nomyces viscous and faeces from caries-active Osborne-Mendel rats, which were placed on calculus diet 580F supplemented with 0.2% P as Na 2 PO 4. The placebo and test mouthwash were each applied to cheek teeth in a group of 12 such rats twice daily Monday through Friday and once daily Saturday and Sunday for 25 days per 30 day ode. The animals are weighed at the beginning and end of the study to ensure that the rats remain in an otherwise normal state. At the end of the period, tartar formation is assessed by routine methods and the following results are found: 3 0 35

Claims (6)

1. Essentially anhydrous mouthwash, which is free of discolouration-inducing antibacterial antibacterial agents and comprises an orally acceptable carrier, and in an effective amount as an antitandarstensic agent at least one bis (o-carboxyphenyl ester of a C2-8 aliphatic dicarboxylic acid. A mouth care agent according to claim 1, characterized in that the anti-tartar agent is bis (o-carboxyphenyl) succinate. 35 Mouthpiece according to claim 1 or 2, characterized in that it contains by weight approx. 0.01% to 10% of anti tartar blend. DK 162419 B IB Oral care product according to claim 1 or 2, characterized in that it contains by weight approx. 0.05 to 5% of the anti-tartar agent. Mouthpiece according to claim 1 or 2, characterized in that it is a mouthwash liquid containing a liquid carrier and which in aqueous medium has a pH value of approx. 3.5 to approx. 8th 5 Mouth cloud1 liquid 12 135 g 14.8 α <0.01 (0.1% BOCS) * 20 risk units 10. The term "risk units" means "units" tooth surfaces, with each tooth having multiple surfaces. "20 units of risk" means that each rat in the test has 20 tooth surfaces, on which there is a tendency to form tartar. The test shows that while the 12 placebo-tested rats developed 17.9 tartar-15 coated tooth surfaces, only the BOCS-tested rats developed 14.8 such tartar-coated surfaces, which is a significant reduction of 3.1 or 17.3%, the above results thus show that BOCS in a quantity of 20 0.1% used topically is clearly effective (within 99% level auet ) to reduce tartar formation by 17.3% compared to the placebo Patent Claim 25 -------------------- 6. A mouth care agent according to claim 1 or 2, characterized in that it is a toothpaste containing a liquid carrier, a gelling agent and a dental acceptable polishing agent, and which in aqueous medium has a pH of approx. 3.5 to approx. 8. 20 25 30 35