CN1090750A - Polymeric anticalculus agents - Google Patents

Abstract

A kind of compositions and method that forms based on the control tartar of copolymer, said copolymer is formed by the monomer that list and dicarboxylic acids vinyl monomer, hypophosphite sources and at least one are selected from other, other monomer wherein comprises, for example sulfonate and carboxylate monomer, the monomer that contains Polyethylene Glycol and cationic monomer.

Description

Polymeric anticalculus agents

The present invention relates to new anticalculus agents, contain the non-food composition of their oral cavity use, and use the method that these compositionss control tartar accumulate on tooth.

Tartar claims that also tartar is by the spontaneous dental plaque of synthos mineralising, and form the most stable and the most difficult synthos of removing is known as hydroxyapatite on the thermodynamics.In this area, it is believed that amorphous calcium phosphate is the precursor of hydroxyapatite, and those materials that disturb hydroxyapatite to form are effective anticalculus agents.

Anionic polymer is in the art as anti-tartar and preventing dental plaque agent.For example, U.S. Pat 4,842 847(Amjad) discloses anti-tartar composite, and these compositionss are based on carboxylic acid homopolymer and copolymer and fluoride ion and can be a kind of inorganic phosphate tooth abrasive material.In U.S. Pat 4,892,725(Amjad) and US4,892, found in 724(Amjad) similarly open.

People such as Gaffar are in U.S. Pat 4,806, disclose a kind of fluorion source of supply, the compositions of linear molecule dehydrated polyphosphate and a kind of synthesizing linear polymer poly carboxylate in 342, US4,806,340, UA4,808,400 and US4,808,401.Be listed in people's such as above-mentioned Gaffar the patent, the synthesizing linear polycarboxylate of Shi Heing comprises unsaturated carboxylic acid olefinic or that ethylene belongs to basically, and that lists comprises acrylic acid and maleic acid.Synthesizing linear polycarboxylate Gantrez S-97 in people's such as Gaffar the patent

1: 1 copolymer of (by GAF Corporation) a kind of maleic acid and methoxy-ethylene is put to the proof explanation.

U.S. Pat 4,661, people such as 341(Benedict) purposes of low-molecular-weight polypropylene acid (MW is in the 3500-7500 scope) in dental composition disclosed.U.S. Pat 3,429 963(Shedlovsky) has been set forth and has been contained maleate copolymer and the purposes of vinyl sulphonate polymer in toothpaste.U.S. Pat 4,183, people such as 914(Gaffar) reported the purposes of poly salt as anticalculus agents.U.S. Pat 4,362 713(Buck) discloses some the hydrophilic alkali metal salts of 1: 1 copolymer of styrene and maleic acid and some linear 1-alkene and 1: 1 copolymer of maleic acid and the ammonium salt purposes as the preventing dental plaque agent.U.S. Pat 4,915,937(Amjad) disclose the compositions that use in the oral cavity of containing fluorine source, tooth abrasive material, Quadrafos and hydrolysis-resisting agent, hydrolysis-resisting agent wherein is selected from the homopolymer of substituted acrylamide homopolymer, unsaturated sulfonic acid and its salt and the homopolymer and the copolymer of cationic monomer.

U.S. Pat 5,011, people such as 682(Elliott) single and dicarboxylic acid monomer's the cotelomer that contains hypophosphites is disclosed, it with by the disclosed polyacrylic acid of people such as Benedict (US4,661,341) compare or by the disclosed poly of people such as Gaffar (salt) (US4,183,914) and to show superior anti-tartar activity.Above-mentioned, ' cotelomer of 682 patent disclosures is to form from list and dicarboxylic acids mixture of vinyl monomer with the hypophosphites radical reaction.The anti-tartar function of these cotelomers is excellent.Yet, as a part of the present invention, found the cotelomer broad incorporation multivalent ion (for example calcium ion) of above-mentioned ' 682 patent disclosures, so that they can be separated, must produce adverse influence to the function and the comfort level of prescription like this.

The result is, needs to obtain aspect the formation of control tartar with ' 682, and the cotelomer of patent is equally effective, but the anti-tartar active matter that the dissolubility in multivalent salts solution improves.In addition, need to improve the robustness of cotelomer, so that more effectively block the adhesion of antibacterial in hydroxyapatite surface in hydroxyapatite surface.

Therefore, an object of the present invention is to provide a kind of deliquescent effective anticalculus agents that improved.

Another object of the present invention provides a kind of effective anticalculus agents that has improved robustness.

Also purpose of the present invention provides the non-food composition that use in the oral cavity of containing copolymer, and copolymer wherein is from forming with the list of hypophosphite sources reaction and dicarboxylic acid monomer and at least a other monomeric mixture.

These and other objects of the present invention can become clearer along with detailed description and embodiment subsequently.

Finish above-mentioned purpose by the present invention, the present invention includes at least a polymer that contains the control of effective dose tartar, the non-food composition that use in the oral cavity with formula I:

A wherein is a polymer residue arbitrarily, and it comprises:

(ⅰ) unit of at least a formula II:

(ⅱ) be different from unitary at least one the formula III unit of formula II:

(ⅲ) be selected from the unit of formula IV, the unit of formula V, the unit of formula IV, or at least one unit of their isomer and their mixture:

Wherein

R ₁, R ₂, R ₃And R ₄Be independently selected from one group of group forming by hydrogen methyl, ethyl group and their coalition;

X is selected from one group of group being made up of hydrogen, alkali metal, alkaline-earth metal, transition metal, ammonium, alkylamine, alkanolamine residue and its mixture;

R ₅Be hydrogen or methyl;

R ₆Be or NR ₁₅, R wherein ₁₅It is the alkyl group of hydrogen or a kind of 1-4 of containing carbon atom;

R ₇It is the straight or branched hydro carbons group that contains 1-12 carbon atom;

R ₈Be selected from-SO ₃X ,-COOX and

Wherein X is as defined above;

R ₉Be O or NH;

R ₁₀And R ₁₁Be independently selected from hydrogen and methyl;

R ₁₂Be selected from-OH-N(R ₁₆) and-OR ₁₇;

R ₁₆, R ₁₇, R ₁₈Be independently selected from hydrogen or contain the hydro carbons group of 1-18 carbon atom;

R ₁₃And R ₁₄Be independently selected from the hydro carbons group that contains 1-18 carbon atom;

And in the formula I, B is hydrogen or residue A, and l, m, n, p and r are the integers that enough provides polymer average weight molecular weight from about 400 to about 5000.

" isomer of formula IV " of the term that uses refers to following structure in this description:

R wherein ₁₃, R ₁₄With r be as defined above.

Disclosed all anticalculus agents form from monocarboxylic acid monomer, dicarboxylic acid monomer, hypophosphite sources and at least a other monomeric mixture among the present invention, and other monomer wherein is selected from the monomer of formula IV, V, VI structure and the isomer of formula VI that can form through reaction.Be present in the various structures that are used for copolymer of the present invention, can in copolymer, adopt various orders.This copolymer can contain the monomer type more than 3 kinds.

It generally is anionic or amphoteric being used for copolymer of the present invention.Typically, the copolymer that comprises formula IV or V structure is anionic, and the copolymer that comprises formula VI structure or its isomer is amphoteric.Owing to comprising selected the third monomer disclosed herein in the cotelomer (after this being called " list/dicarboxylic acids cotelomer ") that contains monocarboxylic acid/dicarboxylic acids hypophosphites, the various character of this cotelomer change easily, have also kept the anti-tartar activity of this cotelomer.

For example, the copolymer of the present invention that comprises formula IV or formula V structure is compared with list/dicarboxylic acids cotelomer and is had improved dissolubility.Improved dissolubility is from practical angle, means the non-food composition that use in the various oral cavities of prescription, and bigger selectivity and degree of freedom are arranged, because in fact reduce and stoped in the mill and the chance of making in the compositions of back that is separated.The more important thing is and in fact reduced or eliminated and to have reduced the danger of anti-tartar function by being separated or relatively poor dissolubility causes.

Comprise formula IV or its isomer and copolymer of the present invention, stoping bacterial adhesion aspect the new hydroxyapatite that forms, single/the dicarboxylic acids cotelomer is more effective.In addition, the ability that these copolymers are attached to the oral cavity protein surface is stronger, and, in the presence of salt, also keeping viscosity even contain the prescription of these copolymers.Therefore, be used for copolymer of the present invention with single/-the dicarboxylic acids cotelomer compares and shows improved effect; Observed identical anti-tartar used when these copolymers produced with use list/dicarboxylic acids cotelomer, and had improved the effect of others.

Term as used in this specification " the non-food composition that use in the oral cavity " refers to be used for the compositions of dental surface.The example of these compositionss has toothpaste, mouth-wash, irrigation, dentifrice and gelinite and other oral cavity transmission medium thing.

The present invention also comprises the method that the control tartar forms, and this method comprises to the oral cavity uses compositions of the present invention.

The non-food composition that use in oral cavity of the present invention comprises at least a copolymer that suppresses composition as essential tartar, this copolymerization contains at least one unit of formula II, at least one unit of formula III, microcosmic salt group, be selected from formula IV, V, VI structure, at least one unit of isomer of formula VI and their mixture.

Form the suitable list of formula II and III and dicarboxylic acid monomer by people such as Elliott, in U.S. Pat 5,011, describe in 682, the document is incorporated herein by reference document in the lump.As mentioned above, ' 682 patent disclosure a kind of cotelomer (list/dicarboxylic acids cotelomer) that contains list and dicarboxylic acid monomer and microcosmic salt group.The proper monomer that forms formula II has single carboxylic acid or salt group, and contains 3-7 carbon atom in optional position.Suitable monocarboxylic acid monomer comprises acrylic acid, methacrylic acid, alpha-substituted alkyl acrylic and propenoic acid beta carboxyalkyl ester.The proper monomer that forms formula III has at least two carboxylic groups and 4-7 carbon atom can be arranged.Suitable monomers comprises maleic acid, fumaric acid, itaconic acid, mesaconic acid, citraconic acid, their anhydride or salt.These groups of setting forth as ' 682 patents are essential to the anti-tartar effect that improves polymer of the present invention.

According to the present invention, this copolymer must comprise other structure, and this structure is selected from the isomer of formula IV, V or VI and formula VI.

Under the preferable case, be used for the chemical compound that contains formula IV of the present invention and have:

R ₆＝N-H

R ₇The alkyl of=2-4 carbon atom; With

R ₈=-SO ₃X or-COOX, X wherein such as above-mentioned.

Because the easy polymerization of these groups, above-mentioned R group is preferred.In addition, be incorporated into the polymeric anticalculus agents of said structure, obviously stop being separated in the saline solution.

Under the preferable case, be used for the chemical compound that contains the formula V of the present invention and have:

R ₅=H or CH ₃R ₁₀=H

R ₉=O R ₁₁=H R ₁₂=OH or OCH ₃

Because its commercial buying and water solublity, formed structure-polyacrylic acid glycol ester (or methacrylate) is preferred.

Better under the situation, be used for the chemical compound that contains formula VI or its isomer of the present invention and have:

R ₁₃=-CH ₃And

R ₁₄＝-CH ₃

Work as R ₁₃And R ₁₄When being methyl substituents, the easy polymerization of chlorination dimethyldiallylammonium of formation, low price and insensitive to PH.

The proper monomer that forms the formula IV structure has (methyl) acrylate or (methyl) acrylamido unsaturated group, has the function side group that contains anionic group, ketone, amino or ammonium group.The monomeric example that can form the formula IV structure through reaction includes but not limited to 2-acrylamido-2-methyl propane sulfonic acid or its salt, sulfophenol methallyl ethers, 3-acrylamido-3 Methylbutanoic acid or its salt, acrylamido alkanesulfonic acid or its salt, alkyl acrylic alkyl amino salt, alkyl methyl acrylic acid alkyl amide, dimethyl aminoethyl methacrylate, diacetone acrylamide amine and alkyl amino alkyl (methyl) acrylamide.

The proper monomer that forms the formula V even more preferably has and is 1-100 ethylene oxide or the unitary side group of propylene oxide.Suitable monomers (for example includes but not limited to polyacrylic acid glycol ester or polymethylacrylic acid glycol ester, methacrylic acid PEG350 ester, methacrylic acid PEG1000 ester, methacrylic acid PEG2000 ester, methacrylic acid 2-hydroxyethyl ester, polymethyl acid propylene glycol ester, polyethylene oxide-altogether-and the propylene oxide methacrylate, N-Polyethylene Glycol (methyl) acrylamide, polyethylene oxide-be total to-propylene oxide (methyl) acrylamide.

The proper monomer that forms formula VI structure has quaternary nitrogen group or charged cation group.The monomeric example that can form formula VI structure through reaction includes but not limited to the dialkyl monohalide allyl-ammonium, for example, and the chlorination dimethyldiallylammonium.When these monomers during polymerization, can form the repetitive of two kinds of different isomeries under polymerizing condition described herein.

The preparation method major part of copolymer of the present invention is known.U.S. Pat 5,011 has been described these basic skills in 682 and US5,077,361, and two pieces of patents are incorporated herein by reference data in the lump.Reaction solution comprises a kind of monocarboxylic acid monomer described above (for example, acrylate), a kind of dicarboxylic acid monomer (as maleate), hypophosphite sources and other monomer.

In order to be incorporated into other monomer easily, preferably improve ' 682 and ' 361 patents in the method described.For example, when other monomer is high molecular, at 200-2000 and bigger, when the monomer that contains Polyethylene Glycol or polypropylene glycol belongs to this situation, is reflected in the relative weak solution medium and carries out to obtain optimum as molecular weight.Contain in Polyethylene Glycol or polypropylene glycol monomer or the monomeric reaction of other high molecular relating to, when percent solids is high, reaction can produce precipitation when finishing soon, and this is likely owing to close reaction in the acid groups of each component of polymer and the hydrogen bond between the ethylene oxide unit.

Reducing the percent solids level is separated to eliminating to more preferably about 15-25% from about 40-50%.

When reaction medium comprises for example when reaction can form the quaternary ammonium salt monomer of formula VI, preferably use another kind of improved method, in reactant liquor, add the PH situation that these monomers change solution, specifically, quaternary ammonium salt improves the pH value of solution, and with the acrylic acid reaction in and acrylic acid.Consequently owing to higher PH, the maleate monomer reactivity is lower, more difficult polymerization.Therefore, when the reaction beginning, add more a spot of sodium hydroxide, and be necessary to monitor more carefully the pH value of solution with the reduction solution PH.

Because the indissolubility of product under low PH, being separated during reaction may appear in the copolymer of the present invention that contains formula VI structure.These materials are amphoteric and may have the isoelectric point, IP that forms pH value near end-product in nature.Under this PH, said copolymer has minimum dissolubility in water.Therefore, must be careful to guarantee to make and reacting completely, unless improve solution ion strength.Otherwise be necessary to neutralize so that the gained substance dissolves.

Before polymerization, the total monomer in the raw material component can be from about 40: 1 to about 1: 1 to the molar ratio scope of hypophosphites; Preferably from about 20: 1 to about 4: 1, best between about 16: 1 to about 7: 1.Monomer causes lower polymer molecular weight and the hypophosphite sources high level in polymer to infiltrate to the low ratio of hypophosphites.

The amount scope of dicarboxylic ester monomer in copolymer from mole percent about 10 to about 95, preferably from mole percent about 20 to about 50.

Form the monomer or the monomer mixture of formula IV, V and/or VI structure through reaction, amount scope in copolymer from about 5 to about 40mole%, preferably from about 10 to about 30mole%, so that keep anti-tartar active and have improved dissolubility and/or an improved robustness to hydroxyapatite.As the following examples explanation, these monomeric materials that have more than 40mole% lose anti-tartar activity.Except that the dicarboxylic acid monomer, all monomers to dicarboxylic acid monomer's ratio within scope from 6: 1 to 1: 6, preferably, most preferred within scope from 4: 1 to 2: 1 within about 5: 1 to 1: 1 scopes.And, contain the anticalculus agents of big monomer (PEG1 for example, 000 and PEG2,000), when the third monomeric content 20% when above, its anti-tartar is active to be reduced.

The molecular weight ranges of copolymer that is used for the present composition is between about 400 to about 5,000, and is preferably between about 800 to about 3,500, most preferred between from about 800 to about 3,000, so that make the anti-tartar of copolymer active maximum.

The amount scope of these copolymers in composition for oral cavity be from about 0.01 to about 10% weight, and preferred about 0.4 to about 7%, and be best between about 1 to about 5%.

The form of the preferred composition for oral cavity of the present invention has toothpaste, tooth frost, gelinite or dentifrice and mouthwash, washes preceding irrigation or washes afterflush agent prescription, chewing gum and lozenge.

The composition that is generally comprised within toothpaste and the gel combination can be used for according in toothpaste of the present invention and the gel combination.Appropriate ingredients comprises grinding-material, foaming agent, aromatic, wetting agent, bonding agent, deodorizer and water.

Mouthwash generally comprises water/alcoholic solution, spice, wetting agent, deodorizer, foaming agent and coloring agent.

The grinding-material that can be used in the present composition comprises aluminium oxide and its hydrate, for example alpha-aluminium oxide trihydrate, magnesium trisilicate, magnesium carbonate, aluminosilicate, for example aluminium silicate of calcination process and aluminium silicate, calcium carbonate, Zirconium orthosilicate., poly-methyl acrylates, powdery polyethylene, silica xerogel, hydrogel and aeroge etc.Suitable grinding agent also has: calcium pyrophosphate, insoluble Polymeric sodium metaphosphate., calcium carbonate, orthophosphoric acid dicalcium, graininess hydroxyapatite etc.The form that the compositions of using according to the oral cavity is taked, the amount of described grinding-material can from 0 to 70% weight, and preferably 1 to 70% weight is preferred from 10-70%(weight), be so especially to toothpaste.

The wetting agent that expectation is used for the present invention comprises glycerol, polyol, sorbitol, Polyethylene Glycol, propylene glycol, partially hydrogenated Polysaccharides etc.The amount from 0 to 80% that this wetting agent is general, preferably from 5-70% weight, like this to toothpaste especially.Be suitable for thickening agent of the present invention and comprise silicon dioxide.The content of thickening agent can be 0.1-20%(weight in toothpaste paste and the gel).

Be applicable to that the bonding agent in the present composition comprises hydroxyethyl-cellulose (Natrosol ), sodium carboxymethyl cellulose and hydroxypropyl cellulose (Klucel

) and xanthan gum, Irish moss and Huang

Natural gum.The content of conjugate in toothpaste of the present invention can from 0.01 to 10%.Be applicable to that the sweeting agent in the present composition comprises glucide, preferred contents level is about 0.1% to 5%.

Suitable foaming agent comprises soap, anion, cation, nonionic, amphoteric and/or zwitterionic surfactant.Its contents level can be at 0-15%, and is preferably at 0.1-15%, preferred in 0.25-10%(weight).

, open in 772 and 4,627,977 as some pyrophosphate of useful anticalculus agents and other polyphosphate in U.S. Pat 4,515.These comprise two-and four-alkali metal pyrophosphate, alkali metal wherein preferentially is selected from sodium and potassium.The amount of the polyphosphate that is comprised should be able to provide at least 0.5% polyphosphate anion usually, and it is about 10% that high energy provides, and preferably provides about 7.5%.

Various anionic polymers can be used as other anticalculus agents and/or preventing dental plaque agent.Suitable polymers comprises the carboxylate polymer, sulfonate polymer, contain sulfonate and carboxylate the part polymer, contain unitary carboxylate polymer of microcosmic salt and their mixture.

, open in 269,4,416,867,4,425,325 and 4,339,432 as the zinc salt of anticalculus agents and preventing dental plaque agent in U.S. Pat 4,100.Preferred compositions of the present invention comprises zinc salt, particularly zinc citrate.The content of this zinc compound will enough provide the zinc of about 0.01%-about 4% in compositions, or better provides about 0.05% to about 1% zinc ion.

The fluorine source that is used for toothpaste can comprise, and for example sodium fluoride, stannous fluoride, sodium monofluorophosphate, zinc ammonium fluoride, stannic fluoride ammonium, calcium fluoride and Cobalt difluoride. ammonium preferably will comprise and produce anti--rolling action, and preferred compositions of the present invention comprises the fluorine source.The fluorion level that provides is generally at about 0-1500ppm, 50-1500ppm preferably, even highly also can use to about 3000ppm level.

Usually the aromatic that in toothpaste, comprises low content, for example from about 0.01 to about 5% weight, especially from about 0.1% to 5%.

Also can comprise antibacterial, for example phenols such as Triclosan

(as Ciba-Geigy) and/or water-soluble antimicrobial such as didextrose pickling BITAI, hexatidine, Win-21904, quaternary amines antimicrobial compound and some metal ion source of water solublity are as zinc, copper, silver and Ya Xi such as zinc chloride, copper chloride, stannous chloride and silver nitrate.

Titanium dioxide is suitable coloring agent.

In dentifrice of the present invention, can use the dyestuff/toner that is suitable for dentifrice, for example FD﹠amp; C blue #1, FD﹠amp; C yellow #10, FD﹠amp; The red #40 of C etc.

Can comprise various other optional ingredients in the compositions of the present invention, for example antiseptic, vitamin such as vitamin C and E, other antiplaque agent such as tin salt, mantoquita, strontium salt and magnesium salt.Can also comprise the PH regulator, resist-carry agent and urea, calcium glycerophosphate, trimethyl sodium phosphate, polysiloxanes, plant extract, to desensitizer and the potassium nitrate and the potassium citrate of sensitive tooth, and their mixture.

Can comprise casein and/or its hydrolyzate and carry agent as anti-, as contents level at 0.01-20% weight, preferably 0.1-10%.

The above-mentioned corresponding compounds of using in toothpaste of mentioning also is suitable for mouthwash in above-mentioned scope, the ethanol content level that mouthwash can comprise can from 0 to 60%, preferably 5 to 30% weight.

Following certain embodiments further proves the present invention, but does not limit the present invention thus.

Embodiment 1

Use hypophosphites control molecular weight, prepare the cotelomer that contains acrylic acid, maleic acid and 2-acrylamido-2-methyl propane sulfonic acid (AMPS).Come anhydride to be dissolved in the deionized water 13 KEMA, transfer PH to about 7.It is that 8: 1 sodium hypophosphite monohydrate is added to the water to the hypophosphites molar ratio that quantity enough provides final monomer.This solution is heated to about 85 ℃.Finish reaction by the initiator that slowly adds simultaneously and other monomer.With sodium peroxydisulfate (accounting for the 1.5mole% of the total monomer of adding) initiated polymerization.This initiator slowly adds in entire reaction course (4.5 hours).Surpass after 4 hours, add the 12g acrylic acid and the 6.83g AMPS that are dissolved in the deionized water.Reaction lasts till that acquisition reaches 100% basically and transforms.If desired, about 10 ℃ of final 30-60 minute rising reaction temperature, to remove the remaining monomer of trace.If desired, add the initiator of additional quantity to remove the remaining monomer of trace.Reaction is monitored by HPLC, when residual monomer (acrylic acid and maleic acid) be lower than after measured about think 0.1% the time react completely.

Embodiment 2

Use sodium hypophosphite control molecular weight to prepare the cotelomer that contains acrylic acid, maleic acid and 3-acrylamido-3 Methylbutanoic acid (AMBA).Except replacing with AMBA the AMPS, other adopts the method identical with embodiment 1.Wherein use AMBA5.64g.

Embodiment 3

Use sodium hypophosphite control molecular weight to prepare the cotelomer that contains acrylic acid, maleic acid and single polyalkylene glycol acrylate 200 esters (PEGA200).(6.52g) is dissolved in the deionized water with maleic anhydride, transfers PH to about 7, and it is that 8: 1 sodium hypophosphite monohydrate is added to the water to the hypophosphites molar ratio that quantity enough provides final monomer.This solution is heated to about 85 ℃.With sodium peroxydisulfate (accounting for the 1.5mole% that adds total monomer) initiated polymerization.This initiator adds in entire reaction course (4.5 hours).Simultaneously, above adding 6g acrylic acid and the 3.3gPEGA200 that is dissolved in the deionized water after 4 hours.Reaction lasts till that reaching 100% basically transforms.If desired, about 10 ℃ of final 30-60 minute rising reaction temperature, to remove the remaining monomer of trace, if desired, the initiator that adds additional quantity is to remove the remaining monomer of trace.

Embodiment 4

Use sodium hypophosphite control molecular weight to prepare the cotelomer that contains acrylic acid, maleic acid and single polyalkylene glycol acrylate 2000 esters (PEGA2000).Maleic anhydride (1.57g) is dissolved in the deionized water, transfers PH to about 7, and it is that 8: 1 sodium hypophosphite monohydrate is added to the water to the hypophosphites molar ratio that quantity enough provides final monomer, and this solution is heated to about 85 ℃.With sodium peroxydisulfate (accounting for the 1.5mole% that adds total monomer) initiated polymerization.This initiator adds in entire reaction course (4.5) hour.Simultaneously, surpass after 4 hours, add the 1.44g acrylic acid and the 8.0g PEGA2000 that are dissolved in the deionized water.Reaction lasts till that reaching 100% basically transforms.If desired, about 10 ℃ of final 30-60 minute rising reaction temperature, to remove the remaining monomer of trace, if desired, the initiator that adds additional quantity is to remove the remaining monomer of trace.

Embodiment 5

Prepare the cotelomer that contains acrylic acid, maleic acid and dimethylaminoethyl acrylate methyl base ammonia ethyl ester (DMAEMA) with sodium hypophosphite control molecular weight.Do not add the AMPS except adding DMAEMA, other adopts the method identical with embodiment 1, wherein uses DMEAMA 5.18g.

Embodiment 6

Prepare the cotelomer that contains acrylic acid, maleic acid and chlorination dimethyldiallylammonium (DMDAAC) with sodium hypophosphite control molecular weight, replace the AMPS except using DMDAAC, other adopts the method identical with embodiment 1.Wherein use DMDAAC 5.31g.

Embodiment 7

Prepare the cotelomer that contains acrylic acid, maleic acid and diacetone acrylamide (DAAM) with sodium hypophosphite control molecular weight.Do not add the AMPS except adding DAAM, other adopts the method identical with embodiment 1.Wherein use DAAM5.58g.

Embodiment 8

Table 1,2,3 has been summed up the compositions of various cotelomers

Table 1

Acrylic acid (AA) and maleic anhydride (MA) and 2-acrylamide

The terpolymer of base-2-methyl propane sulfonic acid (AMPS)

Monomer molar percent

Example AA MA AMPS monomer: inferior phosphorus

Acid salt ratio

AMPS 541-1 0.5 0.4 0.1 8:1

AMPS 541-2 0.5 0.4 0.1 16:1

AMPS 541-3 0.5 0.4 0.1 32:1

AMPS 442-1 0.4 0.4 0.2 8:1

MPS 442-3 0.4 0.4 0.2 32:1

AMPS 145-1 0.1 0.4 0.5 8:1

Acrylic acid (AA) and maleic anhydride (MA) and 3-acryloyl

The terpolymer of amino-3 Methylbutanoic acid (AMBA)

Monomer molar percent

Example AA MA AMBA monomer: inferior phosphorus

Acid salt ratio

AMBA 541-1 0.5 0.4 0.1 8:1

AMBA 541-2 0.5 0.4 0.1 16:1

AMBA 541-3 0.5 0.4 0.1 32:1

AMBA 442-1 0.4 0.4 0.2 8:1

AMBA 442-3 0.4 0.4 0.2 32:1

AMBA 145-1 0.1 0.4 0.5 8:1

Table 2

Acrylic acid (AA) and maleic anhydride (MA) and two

The terpolymer of acetone alkene amide (DAAM)

Monomer molar percent

Example AA MA DAAM monomer: inferior phosphorus

Acid salt ratio

DAAM 541-1 0.5 0.4 0.1 8:1

DAAM 541-2 0.5 0.4 0.1 16:1

Acrylic acid (AA) and maleic anhydride (MA) and methacrylic acid

The terpolymer of dimethylamino ethyl ester (DMAEMA)

Monomer molar percent

Example AA MA DMAEMA monomer: inferior phosphorus

Acid salt ratio

DMAEMA 541-1 0.5 0.4 0.1 8:1

Acrylic acid (AA) and maleic anhydride (MA) and chlorination diformazan

The terpolymer of base diallyl ammonium (DMDAAC)

Monomer molar percent

Example AA MA DMDAAC monomer: inferior phosphorus

Acid salt ratio

DMDAAC 541-1 0.5 0.4 0.1 8:1

DMDAAC 315-1 0.33 0.11 0.56 8:1

Table 3

Acrylic acid (AA) and maleic anhydride (MA) and polyacrylic acid second

The terpolymer of glycol 200 esters (PEGA200)

Monomer molar percent

Example AA MA PEGA200 monomer: inferior phosphorus

Acid salt ratio

PEGA 200 541-1 0.5 0.4 0.1 8:1

PEGA 200 541-2 0.5 0.4 0.1 16:1

PEGA 200 541-3 0.5 0.4 0.1 32:1

PEGA 200 442-1 0.4 0.4 0.2 8:1

Acrylic acid (AA) and maleic anhydride (MA) and polyacrylic acid second two

The terpolymer of alcohol 2000 esters (PEGA2000)

Monomer molar percent

Example AA MA PEGA2000 monomer: inferior phosphorus

Acid salt ratio

PEGA 2000 541-1 0.5 0.4 0.1 8:1

PEGA 2000 541-2 0.5 0.4 0.1 16:1

PEGA 2000 541-3 0.5 0.4 0.1 32:1

PEGA 2000 442-1 0.4 0.4 0.2 8:1

Embodiment 9

Table 4 has been summed up the molecular weight of various polymer, remaining monomer and percent solids.

Table 4

Monomer example % solid molecular weight is remaining

M _wM _nMWD AA MA

AMPS 541-1 45 1660 800 2.1 0.01% 0.05%

AMPS 541-2 42 4300 1200 3.6 0.01% 0.04%

AMPS 541-3 43 12.1K 1900 6.5 0.01% 0.3%

AMPS 442-1 24 1600 800 2.0 0.01% 1.3%

AMPS 442-3 50 9300 2500 3.8 0% 0.8%

AMPS 145-1 22 2400 1100 2.2

AMBA 541-1 45 2000 900 2.4 0.06% 0.20%

AMBA 541-2 41 4700 1600 2.9 0% 0.01%

AMBA 442-1 21 1500 800 1.9 0.1% 2.1%

AMBA 145-1 14 2000 900 2.2 0.1% ---

DAAM 541-1 45 1500 800 1.9 --- ---

DAAM 541-2 42 4000 1400 2.9 0% 0.04%

DMAEMA 541-1 52 1000* 0.004%

0.003%

DMDAAC 541-1 -- 1500* --- --- 0% 0%

DMDAAC 315-1 1500*

PEGA 200 541-1 41 1400 800 1.8 0.002%

0.001%

PEGA 200 541-2 41 3000 1600 1.9 0.03% 0.77%

PEGA 2000 541-1 14 3000* --- --- 0.8% 1.9%

PEGA 2000 541-2 21 5000* --- --- --- ---

PEGA 2000 541-3 24 10000* --- --- --- ---

PEGA 2000 442-1 22 15000* --- --- --- ---

* the molecular weight of Gu Jiing.

Embodiment 10

Tested the copolymer that is used for the present composition and stoped the ability of amorphous calcium phosphate to the hydroxyapatite conversion, this point is counted as the anti-active sign of tartar in the art.The PH-stat that adopts U.S. Pat 4,627,977 embodiment 1 to describe tests described cotelomer.Represent higher activity long time delay.Be used in U.S. Pat 5,011, disclosed list/dicarboxylate cotelomer is made comparisons, is shown with AM-C in 682.The gained result is summarized in the table 5:

Table 5

PH-Stat test: the comparison of different polymer

Sample dose time delay (minute)

AM-C 15ppm ≈6.0-7.5

AM-C 10ppm 4.8

AM-C 20ppm 12.2

AMPS 541-1 15ppm 6.6

AMPS 442-1 15ppm 7.3

AMPS 145-1 10ppm 0.0

AMBA 145-1 10ppm 0.0

AMBA 541-1 15ppm 5.7

AMBA 442-1 15ppm 4.8

DAAM 541-1 15ppm 7.0

PEGA 200 541-1 10ppm 5.4

PEGA 200 541-1 20ppm 16.0

DMDAAC 541-1 10ppm 5.1

DMDAAC 541-1 20ppm 12.0

DMAEMA 541-1 10ppm 4.6

DMAEMA 541-1 20ppm 12.0

Polyacrylic acid 20ppm 0.0

MW 60,000

Gantrez S-97

⁽¹⁾20ppm 0.0

(1) 1: 1 copolymer MW700 of maleic acid and methyl vinyl ether, 00(such as GAF).

The result shows in the table 5, is used for copolymer of the present invention stoping amorphous calcium phosphate to the hydroxyapatite conversion aspect, and is the same effective with list/dicarboxylate cotelomer (AM-C).

As in U.S. Pat 4,627, disclosed in 977, find polycarboxylate copolymer (polyacrylic acid) and Gantrez

Non-activity.Also find to contain mole percent and be higher than 40% the third monomeric material (AMPS145-1, AMBA145-1) the anti-tartar activity of nothing.

Embodiment 11

Dissolubility and crystal growth suppress active contrast and are presented in the table 6.Dissolubility is tested in the solution of increase Ca concentration represented as table 3.The crystal growth inhibitory action is measured by the crystal growth inhibition test that adds the hydroxyapatite nucleus.Description among this paper U.S. Pat 5,011,682 embodiment 5 is as a reference being listed in this test in the lump in.Sample is to carry out for 0.1% time at PH=8.0 and dose of polymer.

The result shows that the anion terpolymer (as AMPS, AMBA and PEGA copolymer) in the scope of the invention compares with list/dicarboxylic acids cotelomer and have improved dissolubility (for example improved tolerance limit in calcium solution).Simultaneously, similar with molecular weight aspect the crystal growth list/the dicarboxylic acids cotelomer is the same effective stoping for these anionic polymers.A unitary copolymer (not showing improvement and dissolubility) that only contains formula VI structure in the scope of the invention as DMAEMA and DMDAAC.

As embodiment 10, the third monomer molar percent is higher than 40% material (DMDAAC) and has the activity of reduction.

High-molecular weight non-modification polycarboxylate (acrylate/maleate copolymer of molecular weight 50,000) activity is also relatively poor.Molecular weight is higher than 15,000 copolymer (PEGA2000 541-3) and contains the copolymer that weight is higher than 20% macromonomer of polymer weight and also has the activity of reduction.Along with the raising of Ca concentration, have and reduce the anti-active tendency of tartar.

Table 6

Calcium: polymer repeat unit molar ratio effect

% suppresses (dissolubility) ¹

Polymer 0.5:1 4:1 8:1

AM-C,MW 1200 100(s) 100(i) 100(i)

AM-H,MW 8,400 9(s) 98(i) 94(i)

Sokalan CP-7

MW 50,000 ²92(i) 30(i) 28(i)

Polyacrylate,MW 5000 ³26(s) 100(i) 84(i)

Polyacrylate,MW 60,000 ⁴22(s) 27(i) 29(i)

AMPS 541-1 89(s) 100(s) 100(i)

AMBA 541-1 90(s) 100(s) 100(s)

DMAEMA 541-1 97(i) 100(i) 100(i)

DMDAAC 541-1 94(i) 100(i) 100(i)

DMDAAC 315-1 42(s) 64(i) 42(i)

PEGA 200 541-1 91(i) 100(i) 100(i)

PEGA 2000 541-1 77(s) 79(s) 81(s)

PEGA 2000 442-1 9(s) 12(s) 12(s)

PEGA 2000 541-2 70(s) 73(s) 73(s)

PEGA 2000 541-3 9(s) 12(s) 11(s)

* 1 i-does not dissolve, and partial polymer takes place to be separated,

S-is dissolved, does not have the generation that is separated.

2: 1 acrylate/maleate copolymers that 2-gets from BASF.

The Sokalan PA25PN that 3-gets from BASF

The Acrysol A-1 that 4-gets from Rohm and Haas

Embodiment 12

Measure the dissolubility and the crystal growth inhibitory action of various polymer.Use with embodiment 11 in the identical method of description.

Gained is the result be summarised in the table 7.

Table 7

HAP SCGI result, PH8.0,0.1% dose of polymer

Change Ca: polymer repeat unit molar ratio structure is to inhibiting influence

% suppresses (dissolubility) ¹

Polymer 0.5:1 4:1 8:1

AMPS 541-1 89(s) 100(i) 100(i)

AMPS 145-1 61(s) 53(s) 81(s)

AMBA 541-1 90(s) 100(i) 100(i)

AMBA 145-1 79(s) 83(s) 85(s)

DMDAAC 541-1 94(i) 100(i) 100(i)

DMDAAC 315-1 42(s) 64(i) 42(i)

Table 7 presentation of results in containing acrylate, maleate and the third monomeric copolymer, contains and is less than the third monomeric copolymer of 40% and suppresses crystal growth aspect and in fact be better than containing and be higher than the third monomeric copolymer of 40%.

Embodiment 13

Studied various copolymers in the scope of the invention and the list/dicarboxylic ester copolymer prevention bacterial adhesion ability to the hydroxyapatite.

Used following method, adopt the shop to be coated with hydroxyapatite 96 hole elisa plate (cores, tissue culture treated) test, be used for the effect of monitoring polymer to microorganism adhering, form hydroxyapatite coating layer by the sedimentary method of the calcifying solution that contains isopyknic two kinds of buffer, a kind of in two kinds of buffer is 15mM phosphate (KH ₂PO ₄, Fisher), 0.2M triethanolamine (Ficher); Another kind is 5mM calcium (CaCl ₂2H ₂O, Fisher), 0.2M triethanolamine (Fisher).Two kinds of buffer are by transferring PH to 7.4 to make with deionization ultrafiltration water and concentrated hydrochloric acid (Fisher).Two kinds of solution of gained directly mix before use to form supersaturation Ca/PO ₄Solution, this solution does not during preparation at room temperature precipitate.

Each five equilibrium sample (370 μ l) of calcifying solution is added in each hole of microdroplet plate, and this plate placed 80 ℃ of baking ovens 1 hour.Discard the calcifying solution of post precipitation, fill again with fresh solution to each hole, plate places 80 ℃ baking oven again.Through four post precipitations, take out plate, fully wash with distilled water, and make it at room temperature dry.

This process has formed the precipitation that is confirmed to be acceptable single hydroxyapatite.

By using synthetic saliva (1mM phosphoric acid, PH6.8(KH ₂PO ₄, K ₂HPO ₄, Fisher), 50mM KCl(Fisher), 1mM CaCl ₂2H ₂O(Fisher, 0.1mM MgCl ₂(Fisher)) their method preparation of rinsing is used for the plate of adherence test.Handled 1 hour down at 37 ℃ with the synthetic saliva of 370 μ l in each hole, is accompanied by on the rotary shaker dish and stirs gently, then with distilled water rinsing three times.Then, contain 1000 or the synthetic saliva of 100ppm all ingredients, handled 1 hour down at 37 ℃ with every hole 370 μ l.Finish No. three distilled water rinsing post processings.

Streptococcus sanguis G9B have [methyl]- ³H thymidine (every 10ml medium 010 μ Ci Amersham) exists down, tryptone-yeast fructose medium (2.5%Trypticase peptone [BBL], at 1.5% yeast extract [BBL], 0.5%K ₂HPO ₄[Fisher], 0.1% MgSO ₄In [Fisher]).In 37 ℃ of following one nights of growth.With this culture centrifugal (2000xg, 10 minutes), wash twice and be suspended in again in the synthetic saliva optical density (540nm) to 1.5, represent that by this optical density of Petroff-Hauser device counting the S.Sanguis cell concentration is every milliliter 7.9 * 10 ⁹Individual.These suspensions further are diluted to every milliliter of synthetic saliva 2 * 10 ⁸Individual cell adds 300 these suspensions of μ l in each hole.Sheets thus obtainedly under 37 ℃, placed incubator 1 hour, reuse distilled water rinsing three times.

Then add 1N NaOH in each hole, the five equilibrium sample of 10mM EDTA tetrasodium salt (300 μ l), this plate place 37 ℃ incubator 1 hour once more.Remove sodium hydroxide solution with the 1ml tuberculin syringe with 25 gauge needle, therefrom shift out, the oblique angle places scintillation vial quantitative with scintillation counter.Ratio with sample that contains the polymer treatment agent and control sample calculates " adhere to and reduce percentage rate ".

Gained is the result be summarised in the table 8.

Table 8

Copolymer is to sticking to hydroxyapatite surface

The effect of Streptococcus sanguis

Polymer concentration adheres to and reduces percentage rate

None -- 0%

AM-C 100PPM 73%

1000PPM 70%

AMPS 442-1 100PPM 71.3%

1000PPM 81.7%

DMDAAC 541-1 100PPM 91.8%

1000PPM 80.8%

DMDAAC 315-1 100PPM 81.8%

1000PPM 86.2%

PEGA 200 541-1 100PPM 77.4%

1000PPM 74.7%

PEGA 200 541-2 100PPM 75.2%

1000PPM 65.7%

Table 8 is the result show, various copolymers and AM-C in the scope of the invention are attached to hydroxyapatite surface effectively, and block follow-up bacterial adhesion.Data show that copolymer should have improved affinity to the tartar of new formation, thereby stop the further calcification on the surface of its growth.And the anticalculus agents polymer that is adsorbed should reduce the accumulation of antibacterial, and this antibacterial is the core of crystal further growth of the liquid-solid interface of tartar.

The result shows that when low concentration (100ppm), the amphiphilic polymers in the scope of the invention is compared the robustness that shows the increase of hydroxyapatite surface with AM-C.

Embodiment 14

A representative formula that contains polymeric anticalculus agents of the present invention is as follows:

Formulation of tooth-paste (PH=5-9)

The percetage by weight of ingredients constitute final composition

70% sorbitol (by Roquette) 64.0%

The silicon dioxide of abrasive action is arranged, and (Gasil 10%

200

By Crosfield Chemicals)

(Sident 225 for multiviscosisty silicon dioxide

9.0%

By Degussa)

Polymeric anticalculus agents 5.0%

Polyethylene Glycol (PEG32

By Union 5.0%

Carbide）

Sodium lauryl sulphate (Stepanol WA-1.5%

100 By stepan)

Sodium saccharinate (by PMC Specialties) 0.3%

Spice 1.0%

Sodium fluoride (by phil Bro chem) 0.24%

Antiseptic (benzoate) 0.08%

Dyestuff＜.01%

Sodium carboxymethyl cellulose (by Aqualon) 0.15%

Water to 100%

Embodiment 15

A representative formula that contains polymer mouthwash of the present invention is as follows:

Mouthwash prescription (PH=6.5)

The percetage by weight of ingredients constitute final composition

Ethanol 12.5%

70% sorbitol (by Roquette) 7.0%

Polymeric anticalculus agents 5.0%

Polysorbas20 (by ICI) 0.55%

Antiseptic (parabens) 0.2%

Spice 0.1%

Dyestuff＜.1%

Sodium saccharinate (by PMC specialties) 0.65%

Sodium chloride 0.05%

Sodium acetate 0.015%

Acetic acid 0.015%

Water to 100%

Unless among description and the embodiment indicated outside, the material in the description of the present invention is buied from following supplier:

The materialman

Acrylic acid Aldrich

Maleic acid Aldrich

AMPS Lubrizol

AMBA Chemie Linz

PEGA 200，2000 Monomer，Polymer & Dajac Labs

DMAEMA Alcolac

DMDAAC CPS

DAAM Monomer，Polymer & Dajac Labs

Sodium hypophosphite hydrate Aldrich

Sodium peroxydisulfate Aldrich

It only is representational needing the clear particular form of the present invention that illustrates and describe herein.The various variations that available illustrative embodiment includes but not limited in this description to be advised, and do not deviate from the clear elaboration of this description.Therefore need with reference to the appended claim in front, to determine four corner of the present invention.

Claims (14)

1, the non-food composition in oral cavity of the polymer that forms of a kind of control tartar that contains at least a effective dose, the said polymer has the structure of formula I:

A wherein is a polymer residue arbitrarily, and it comprises:

(i) construction unit of at least one formula II:

(ii) be different from the construction unit of formula II, the construction unit of at least one formula III:

(iii) be selected from a construction unit of formula IV, a construction unit of formula V, a construction unit of formula VI, at least one unit of a kind of isomer of formula VI and their mixture:

Wherein, R ₁, R ₂, R ₃And R ₄Be hydrogen, methyl, ethyl group or their conjugate;

X is selected from hydrogen, alkali metal, alkaline-earth metal, transition metal, ammonium, alkylamine, alkanolamine residue and composition thereof;

R ₅Be hydrogen or methyl;

R ₆Be O or NR ₁₅, R wherein ₁₅It is the alkyl group of hydrogen or a kind of 1-4 of containing carbon atom;

R ₇It is the straight or branched hydro carbons group that contains 1-12 carbon atom;

R ₈Be selected from-SO ₃X ,-COOX and

Wherein X is as defined above;

R ₉Be O or NH;

R ₁₀And R ₁₁Be selected from hydrogen and methyl respectively;

R ₁₂Be selected from-OH ,-N (R ₁₆) ₂With-OR ₁₇

R ₁₆, R ₁₇, R ₁₈Be selected from the hydro carbons group that contains 1-18 carbon atom respectively,

R ₁₃And R ₁₄Be selected from the hydro carbons group that contains 1-18 carbon atom respectively;

B is hydrogen or residue A, and l, m, n, p and r are that enough to provide polymer average weight molecular weight be about 400 to about 5,000 integer.

2, the compositions of claim 1 wherein is selected from a construction unit of formula IV, a construction unit of formula V, and the isomer of a construction unit formula VI of formula VI or the content of polymer unit in the combination group of their mixture are no more than 40mole%.

3, the compositions of claim 1, polymer wherein contains the construction unit of the formula III from 10mole% to 95mole%.

4, the compositions of claim 1, wherein with the relative molar ratio scope of ((monomers of all monomer-formula III that exist in the polymer)/or the monomer of III) expression from about 6: 1 to about 1: 6.

5, the compositions of claim 1, polymer wherein contains formula IV, and formula IV is to form from being selected from following group: 2-acrylamido-2-methyl propane sulfonic acid or its salt, 3-acrylamido-3 Methylbutanoic acid or its salt, acrylamido alkanesulfonic acid or its salt, alkyl amido acrylate, alkyl amino alkyl methacrylate, dimethyl amino ethyl methacrylate, diacetone acrylamide and alkyl amino alkyl (methyl) acrylamide.

6, the compositions of claim 1, polymer wherein contain the formula V, the formula V is to form from being selected from following monomer: polyacrylic acid ethanol ester, polymethylacrylic acid glycol ester, polymethyl acid propylene glycol ester, polyethylene oxide-be total to-propylene oxide methacrylate, N-Polyethylene Glycol (methyl) acrylamide, polyethylene oxide-be total to-propylene oxide (methyl) acrylamide.

7, the compositions of claim 1, polymer wherein contains the formula IV structure, and IV forms from the dialkyl monohalide allyl-ammonium.

8, the compositions of claim 1, polymer molecule weight range from 800 to 4,000 wherein.

9, the compositions of claim 1, the content of polymer wherein account for the weight range from about 0.1 to about 10% of compositions.

10, the compositions of claim 1 also comprises and reduces the fluorine source of carrying effective dose.

11, the compositions of claim 1, the whole monomers that wherein are used to prepare polymer to the molar ratio scope of hypophosphite sources from about 40: 1 to 4: 1.

12, the compositions of claim 1, compositions wherein are a kind of toothpaste and comprise a kind of grinding-material.

13, the compositions of claim 1, compositions wherein also comprises a kind of zinc ion source.

14, a kind of method of controlling tartar, this method comprises the compositions-treated tooth of using according to claim 1.