CN106456514A

CN106456514A - Methods for protecting and repairing enamel

Info

Publication number: CN106456514A
Application number: CN201580031104.1A
Authority: CN
Inventors: W·A·麦克黑尔; D·G·布朗
Original assignee: First Dental Product Co
Current assignee: First Dental Product Co; Premier Dental Products Co
Priority date: 2014-04-11
Filing date: 2015-04-10
Publication date: 2017-02-22
Also published as: AU2015243217A1; EP3128999A1; EP3128999A4; WO2015157675A1; CA2945330A1; CA2945330C

Abstract

A method of treatment for enamel with substantially aqueous-free, enamel protectant and repair brushing gels containing: stannous fluoride, calcium and a substantivity agent comprising: an emulsion of polydimethylsiloxane in a nonionic surfactant, wherein substantivity of said stannous fluoride and calcium into biofilm present on enamel is enhanced through calcium binding shifting from bidentate to monodentate in the presence of stannous fluoride; and said brushing gels have substantially improved, enamel protectant factor (EPF) and enamel repair factor (ERF) values compared to fluoride brushing treatments with comparable or higher fluoride levels.

Description

Enamel protection and restorative procedure

Technical field

The present invention relates to adamantine protecting and repair by applying anhydrous stannous fluoride to enamel and brushing gel and improve Multiple；Wherein protect and repair composition and to enamel surface, there is affinity, thus extending the stannous fluoride with improvement The protection of effect and repair process.The pass key protection using in the methods of the invention and reparation combination include brushing gel, described Brush gel to comprise：Stannous fluoride in anhydrous affinity agent and calcium.

Background technology

The use of the fluoride in the anticariogenic agent product that the U.S. sells is in the fluoride monograph of FDA Carry out under the guide of 21CFR355.10 (on April 1st, 2012 revision).

Form 1

According to federal register 21CFR 355.10, the concentration of stannous fluoride and consumption in dentifrice/collutory/gel products

Dentifrice

Fluoride dentifrice have been shown as in many clinical trials effective caries preventive agent [Stookey, J.Dent.Res.1990,69 (special issue):805-812], and be considered as the master that is remarkably decreased of caries prevalence rate of many developed countries Want reason.As delivering local fluoride and obtaining the major way of preventing decayed tooth benefit, it is each that dentifrice has been widely used in the world Ground.

Composition is repaired from the protection of enamel surface " flushing " various enamel and enamel by saliva stream, final control is used Various commercially available fluoride enamel in the inventive method protects the effective time of staying scrubbing composition with enamel reparation.For The protection of improvement enamel and enamel repairing effect, commercially available professional prescription class fluoride is scrubbed composition and is employed high-load Fluoride, is 5000ppm for Rx (prescription class) toothpaste, gel and collutory, and for " on dental chair " (" in- Chair ") professional application varnish, can reach the fluoride of about 22000ppm.Additionally, in the fluoride monograph of FDA, mark Accurate OTC (over-the-counter) class (OTC) fluoride dental cream can contain the up to fluoride of 1500ppm.

The Vehicles Collected from Market that fluoride brushes product includes：It is non-that the mouth care fluoride of professional and consumer is processed Prescription class (OTC) and prescription class (Rx) brush product；Including：Toothpaste, gel, paste and varnish.As described above, Rx fluoride tooth The content of fluoride of cream and Rx fluoride dental cream is far above the fluoride monograph content containing up to 5000ppm fluoride.Clinical The professional mouth care fluoride varnish using contains the fluoride being up to about 22000ppm, and OTC fluoride dental cream can contain The up to fluoride of 1150ppm, is the highest content of monograph defined.

ADA (ADA), Food and Drug Administration (FDA) and mouth care professional, including：Full section doctor Life, prothodontists, orthodonticies doctor, department of pediatrics dentist etc., generally speaking, generally compare and are concerned about becoming of content of fluoride increase Gesture.These tissues and mouth care professional generally prefer that in the various Clinical Processing for patient and various OTC and Rx, mouth Using the fluoride of lower content, the enamel realized using relatively low content of fluoride in chamber nursing, the home care of local Protection and repairing effect are suitable with the result that the brushing product with higher content of fluoride is reported.This for more less fluorinated The preference of the brushing product of thing content is based on the load to the toxicity being exposed to high content of fluoride for a long time and child's fluorosiss etc. The heart.

Everybody it is generally recognized that scrub used in process about 90% fluoride in OTC and Rx fluoride at present Spued after a procedure.Therefore, the time processing for adamantine fluoride is basically limited to fluoride and is brushed to enamel On time.By contrast, the adamantine fluoride containing 22000ppm fluoride is applied to by mouth care professional Varnish is designed to maintain at a relatively high content of fluoride on enamel after patient spues.

Fluoride varnish is generally applied in professional mode, frequency be about every six months once, target subject mainly includes Child.

Due to the fluoride in the fluorination drinking water and water in preparing for food etc., meals content of fluoride gradually increases Plus.Additionally, most consumers use fluoride：Toothpaste, collutory, gel etc..Substantial amounts of literature cite is pointed out, local is fluorinated Thing processes and processes more effectively than systemic fluoride in terms of protection and repairing dental enamel.

Referring to：Ripa,Public Health Dent.,1991；51:23-41.

However, with the use of all these fluorides, dental caries continue to propose challenge to child and adult, including old The dental caries of year people, the dental caries of xerostomia patient, the dental caries of immune deficient patients and be medically treated or dental procedure trouble Dental caries of person etc..

Need to improve the dentium nitor quality guarantee of professional mouth care, fluoride process and the OTC fluoride processing for patient Shield and enamel restorative procedure, reduce the risk related to being exposed to high content of fluoride simultaneously.

Furthermore, it is necessary to improve effect that fluoride processes in enamel protection and enamel reparation field, wherein various Effect that fluoride is processed is assessed as the function of the content of fluoride for realizing various situation enamel treatments.

Content of the invention

The purpose of the present invention

Offer can improve enamel protection factor (EPF) value and improve the method that enamel repairs coefficient (ERF) value.

The method that offer can improve EPF value and ERF value, the wherein improvement of EPF value and ERF value can be solidifying along with brushing The minimizing of content of fluoride in glue and realize.

Fluoride described by brushing product and prior art with current commercial fluoride is brushed compared with product, provides Process adamantine method, in the case of reducing the content of fluoride brushed in gel, remain to obtain suitable or improvement EPF value and ERF value.

Offer can improve the method that EPF and ERF of " excessive risk " patient brushes gel.

The method that offer can improve the enamel defect condition of " excessive risk " patient, described patient includes immunodeficiency and suffers from Person, cancer therapy patients, cardiac treatment patient, diabeticss, Cryptogenic organizing pneumonitis (COP) patient etc..

Term defines

Run through the following term description of the feature for describing present invention brushing gel of present specification and claims As follows：

" anhydrous " is defined as：It is substantially free of water.

" enamel protection factor (EPF) " is defined as：The reduction percentage ratio of dental enamel dissolution degree is divided by content of fluoride, fluorine Compound content is recorded using FDA method #40, is represented with 1/1000000th (parts per million, ppm).

" enamel repairs coefficient (ERF) " is defined as：The average increase of enamel fluoride concentration is divided by using FDA side The fluoride that method #33 records brushes the content of fluoride of product.

" stannous fluoride brushing gel " is defined as：In the middle of table 1 above, explained according to federal register 21CFR 355.10 The gel products stated.

" mucomembranous adhesion agent " is defined as：The material of a period of time can be retained on an oral surface, it is easily detected by tongue The mechanism of head or the flowing of saliva and remove.

" stable stannous fluoride " is defined as：When chemical assay, be kept substantially stannous under unreacted state and/or The material composition of content of fluoride.

" biomembrane " is defined as：By antibacterial, the surface adhesion film that forms such as the polysaccharide that oozes out, it is easily detected by mechanical hand Section or saliva are flowed and are removed.

" affinity agent " is defined as：The material composition of the mucosa anelasticity of chemical agent needed for improvement.

" cation bridge joint " is defined as：Two electric attractions between thin film or film layer being caused by cationic moiety.

" calcium combines, from bidentate, the transformation combining to monodentate " is defined as：Class " chelate " loss and calcium that calcium cation combines Single part that cation combines accordingly increases.

" liquid non-ionic surfactant " is defined as：Represent the surface activity in the case of there is not charge species The liquid composition of matter.

" solid-state nonionic surfactant " is defined as：Represent the surface activity in the case of there is not charge species The solid matter composition of matter.

“CaF⁺Part " is defined as：Monodentate calcium fluorion.

" linear polymerization polycarboxylate affinity reinforcing agent " is defined as：There is carboxylate substituent group (carboxylate Substituents linear polymer), it increases anelasticity in powered surfaces for the material composition.

" Emulsion discontinuous phase " is defined as：Submember in the Emulsion being surrounded by continuous phase.

" Emulsion continuous phase " is defined as：Emulsion components around discontinuous phase composition.

Summary of the invention

The present invention relates to processing adamantine method with anhydrous brushing gel component, wherein brush gel in anhydrous affinity agent In contain stannous fluoride and calcium.The method of the present invention brushing gel suitable or more significantly higher than depending on content of fluoride and tooth The existing method of paste composition can more effectively be protected and repairing dental enamel, as shown in the comparison EPF value reported herein and ERF value.

The method of the present invention has unforeseeable enamel protection and enamel repairs characteristic, following article embodiment, table Lattice and accompanying drawing are described in detail；These characteristics owing to applied by brushing uniqueness anhydrous brushing gel component it is characterised in that：

(a) stannous fluoride and calcium；

(b) affinity agent；

C () combines related cation bridge joint to microorganism fluoride.

When enamel protection and enamel reparation brushing gel component are applied on enamel the method, exist in saliva In the case of substantive mucoadhesive gel is formed on enamel；Wherein said mucoadhesive gel is gradually by stable fluorination Stannous and calcium are discharged on enamel.This slow release is continued for, until mucoadhesive gel is finally completely molten by saliva Solution.This gradually release makes fluoride brush " flushing " effect minimum that product is traditionally experienced.The therefore tooth producing Enamel protection and enamel reparation increased EPF value and ERF value, and this is due to extending and being bound to biomembranous microorganism fluorine The related stannous fluoride of compound, the calcium and cation bridge joint time of staying on enamel.Stannous fluoride effect of this improvement Reduce and raise related risk to content of fluoride.

Traditionally it has been reported that being used for processing adamantine method, it depends on the fluorination with intense smell characteristic Thing is brushed product and causes excessive saliva to stimulate, and which increases the speed removing fluoride from mouth.By contrast, the present invention Method depends on brushing to have the gel of special intense smell feature, including " twinge " mouth of the metallic taste covering stannous fluoride Sense and pleasant sensation feature；Have unexpectedly shown that out " time of staying " of increase and extend the effectiveness of stannous fluoride, thus realizing The enamel Absorption of Fluoride more superior than the commercial method relying on stannous fluoride brushing product and enamel protection value are (respectively ERF and EPF).

Brief description

Accompanying drawing 1 outlines and (comprises 970ppm fluoride using having using processing method of the present invention as described in Example 1 Stannous fluoride brushing gel) external enamel protection factor (EPF) value and (a) Rx 5000ppm sodium fluoride toothpaste and The comparison of the EPF value of (b) OTC 1100ppm stannous fluoride toothpaste.

Fig. 2 and Fig. 3 illustrates to process using the present invention of the brushing gel with material composition as described in Example 1 and 2 The enamel of method repairs coefficient (ERF) value；Its stannous fluoride is 970ppm, and is 1100ppm with stannous fluoride respectively, fluorination The toothpaste that sodium is 900ppm or sodium fluoride is 5000ppm compares.

Fig. 4 to 6 shows the present invention process side using the brushing gel comprising material composition as described in embodiment 3 to 5 The ERF value of method.To brush the stannous fluoride content that contains of gels be 970ppm for these of the present invention, itself and (a) 900ppm sodium fluoride Toothpaste, (b) 1100ppm stannous fluoride toothpaste or (c) 5000ppm sodium fluoride toothpaste compare.

Specific embodiment

The enamel protection of the present invention and enamel restorative procedure, brush gel using anhydrous stannous fluoride calcic, its bag Include the affinity agent repairing composition containing various enamel protections and enamel.These affinity agent be used as the protection of various enamels and Repair the carrier of composition.The characteristic of these affinity agent is that they form the energy of mucoadhesive gel in the presence of saliva Power, described mucoadhesive gel has affinity for containing biomembranous enamel.These have the mucosal adhesive of affinity The further characteristic of gel is them：A () can gradually dissolve when being exposed to saliva stream, and (b) dissolves with them, with The protection of various enamels and enamel are gradually repaired composition and are discharged into by unreacted state has biomembranous enamel surface On.This gradually dissolution characteristics of these mucoadhesive gel are by being gradually released to there is biomembranous dentium nitor by these compositions " flushing " impact that saliva repairs composition to enamel protection and enamel is made to be minimized on matter surface.Affinity agent can Extend the enamel protection of the present invention and the persistent period of enamel repair process, and support related to the combination of microorganism fluoride Cation bridge joint, thus improving EPF value and the ERF value of the various processing methods of the present invention, be reduced to simultaneously realize EPF value with The content of fluoride needed for unforeseeable increase of ERF value.

In a preferred embodiment of the invention, brush in gel and include phosphate component.These are existed by Ming Tung United States Patent (USP) 5,037,639；5,268,167；5,427,768；5,437,857；5,460,803；Carry out in the middle of 5,562,895 Description；Published in ADA's foundation (American Dental Association Foundation) by Tung " ACP technology "；Existed by Schemehorn et al.《Clinical dentistry》(The Journal of Clinical Dentistry) Vol.XXII:No 2.51-54,2011；19 lists of references quoted by Schemehorn et al..Can be from New Jersey It is various containing calcium that the international specialty products company (International Specialty Products) of Wei grace obtainsResin (includesM955 it is also described in the middle of description).

The anhydrous affinity agent being applied to processing method of the present invention maintains various enamel protections and enamel to repair composition (bag Include stannous fluoride, calcium and phosphate component) holding is stable and unreacted condition.When this anhydrous affinity agent is exposed to saliva When, it forms mucoadhesive gel, and it has affinity to containing biomembranous enamel.This mucoadhesive gel continues dentium nitor Quality guarantee shield and enamel are repaired composition and are maintained at and have on biomembranous enamel surface, react without composition.These Composition just finally reacts when being discharged on saliva and the coated enamel surface of biomembrane.

Finally, this mucosal adhesive affinity agent is dissolved by saliva completely, and the unreacted enamel of release is protected and enamel Repair balance on the enamel surface that saliva and biomembrane cover for the composition.

Anhydrous brushing gel for processing method of the present invention contains the enamel protection being suitable to protect with repairing dental enamel Repair composition with enamel；Wherein：

(1) described anhydrous gel of brushing suppresses enamel protection and enamel to repair the premature reaction of composition；

(2) pass through saliva to introduce and there is biomembranous enamel, described saliva enamel protection and enamel reparation composition Liquid energy enough dissolves the affinity agent to enamel, dentin, biomembrane and thin film with affinity；

(3) when the solvable affinity agent of saliva carries out saliva dissolving, it is included in enamel protection and the dentium nitor in affinity agent Matter is repaired composition and is gradually released on enamel with unreacted state, and the rate of dissolution of affinity agent is by saliva stream and affinity agent Composition is controlled；With

(4) in the case of there is stannous fluoride, the bidentate of calcium combines the monodentate combination being changed into calcium.

In order to realize the purpose of processing method of the present invention, the solvable anhydrous Emulsion of the saliva as affinity agent is included by solid-state Those Emulsions of polydimethylsiloxanepolymer polymer composition in nonionic surfactant, such as United States Patent (USP) 5,032,387；5, 098,711；5,538,667；5,651,959 when described in；There is following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and between 120 to 150.In preferred embodiments, x=76, y=0 and z=56；

Liquid non-ionic surfactant, has following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and between 125 to 175.In preferred embodiments, x=76, y=25 and z=56；

And the combination of solid-state and liquid non-ionic surfactant, wherein this mixture is liquid.Aforementioned reference It is incorporated herein by.

In a preferred embodiment of the invention, liquid non-ionic surfactant comprises the continuous phase of anhydrous emulsion.This A little liquid non-ionic surfactants are selected from：There is the poloxamer of structure above, and live in this liquid nonionic surface Property agent and solid-state nonionic surfactant mixture；Wherein said mixture is liquid, including：There is structure above Solid-state nonionic surfactant.

For the solvable anhydrous Emulsion of the preferred saliva of the affinity agent of processing method of the present invention include containing liquid non-from Sub- surfactant continuous phase and the anhydrous Emulsion of polydimethylsiloxane (PDMS) discontinuous phase, polydimethylsiloxane (PDMS) range of viscosities of discontinuous phase is about 1500cs to about 2,500,000 cs.It is particularly preferred that anhydrous Emulsion to include liquid non- The ionic surface active agent continuous phase and viscosity discontinuous phase PDMS between 10000cs to 2,500,000 cs.

The solid state surface activating agent of auxiliary agent that can be used as liquid non-ionic surfactant continuous phase is in United States Patent (USP) Have a detailed description in U.S.5651959.The non-tonic surface active agent emulsions mixture of these liquid and liquid/solid is liquid State, and form mucoadhesive gel in the presence of saliva.

Preferably polydimethylsiloxane is selected from the group of the polydimethylsiloxane with following viscosity：1500cs、 10000cs, 100000cs, 250000cs, 500000cs, 750000cs, 1,500,000 cs, 2,200,000 cs, 2,500,000 cs and their group Close.

Foam modifier is beneficial for the processing method of the present invention.These include but is not limited to：Can be used as controlling By the material of amount, thickness or the stability brushing the produced foam of gel component during stirring.Can be subjected to using any oral cavity Foam modifier, including Polyethylene Glycol (PEG), also referred to as polyoxyethylene.The PEG of high molecular is suitable, including average Molecular weight is about those PEG of 200000 to about 7000000, such as mean molecule quantity about 500000 to about 5000000, or About 1000000 to about 2500000.Optionally, one or more PEG is existed with the ratio of about 0.1% to about 10% of total amount, example Such as from about 0.2% to about 5%, or about 0.25% to about 2%.

It is beneficial to apply the wetting agent of the brushing gel in processing method of the present invention to include but is not limited to：Polyhydroxy-alcohol The PEG of (polyhydric alcohol), such as glycerol, Sorbitol, xylitol or low-molecular-weight.In various embodiments, wetting agent can in case Only brushing gel is exposed to and hardens during air.In various embodiments, wetting agent also serves as sweeting agent.

Any other required composition can be added in the material composition being applied to processing method of the present invention, for example, include Other：Taste agent, pH adjusting agent, flavoring agent, sweeting agent, be for example described in United States Patent (USP) No.5776435 those resist micro- lifes Thing (antibacterial) agent, saliva stimulant, antiinflammatory, nutrient, vitamin, protein, antioxidant, coloring agent etc..

Table 2 to table 10 general introduction：

A () uses the processing method of the present invention of brushing gel of heterogeneity as described in embodiment 1 to 5 and commercially available fluoride Brush EPF the and ERF data that product compares；

B () is using the illustrative example of the processing method of the present invention brushing gel；With

C () is using the illustrative process method of the present invention brushing gel.

In a preferred embodiment, the brushing gel that processing method of the present invention is used contains and there is stannous fluoride In the case of based on calcium bidentate combine to calcium monodentate combine transformation and substantially affect enamel protection factor (EPF) and Enamel repairs the composition of coefficient (ERF) value.These compositions include：

Stannous fluoride, calcium and phosphate component,

Affinity agent and affinity reinforcing agent, including：The mixing sodium salt of methyl/vinyl/ether/maleic acid and calcium salt copolymerization Thing；

Wherein stannous fluoride, calcium and phosphate component keep unreacted,

And when being applied to the enamel of saliva cladding, the pH value brushing gel is at least about 3.

The mentioned component that the invention described above processing method is used is discussed in more detail below.

Stannous fluoride concentration

The amount of stannous fluoride used in processing method of the present invention (wherein brush gel and be applied to toothbrush by stannous fluoride (dosage)) so important not as brushing the concentration of available stannous fluoride in gel.Up to the present, have been reported and show, subtract The fluoride concentration brushed in product less is effective not as normal concentration fluoride product.

Petersson,et.al.,Swed.Dent.1982,6:233-238

Metropoulos,et.al.,Community Dent.Health,2002,1:193-200.

Using the processing method of the present invention brushing gel, the unforeseeable EPF value realized and ERF value make it possible to subtract Few stannous fluoride concentration, realizes desirable fluoride protection and assimilation effect simultaneously.

Because fluoride brushes gel absorption, fluoride dosage is important for the enamel fluorosis of less than six years old child 's.For this reason, the amount of the stannous fluoride that minimizing is applied in the middle of using the processing method of the present invention brushing gel is Reduce the preference policy being intended for the stannous fluoride brushing gel dose that less than 6 years old child uses.

Although fluoride brushes product has long-term security history, due to absorbing fluorine in the child below 6 years old Compound and there is give more sustained attention relevant with dental fluorosis.Referring to：Dendrys,J.Am.Dent.Assoc.2000,131(6): 746-755.

Research shows, for 1-3 year child, fluoride brushes 30% to 75% being absorbed of product；For 4-6 year Child, 14% to 48% is absorbed.Warren and Levy,Pediatr.Dent.,199,21:265-271.

The curative effect of the processing method of the present invention and its improvement of brushing gel using stannous fluoride can reduce stannous fluoride The mode of content uses, thus significantly reducing the risk that overdose and fluorosiss occur, provides effective EPF and ERF simultaneously Result.

Referring also to Zero, BMC Oral Health, 2006,6 (Suppl 1):59；1-13.

The fluoride mineral facies being formed using processing method of the present invention are monitored on enamel and is formed in demineraliting culture medium The function of the concentration of middle fluorion [F-]

Referring to：Mohammed,et.al.,Caries Res.,2013；47:421-428.

■ is less than 45ppm [F in the solution^-],¹⁹F MAS-NMR shows that the apatite that fluoride replaces is formed, 1B¹⁹F evil spirit Angle spinning NMR is used for being characterized in the solid phase of precipitation on enamel, during being exposed to external demineralization system as enamel The function of fluoride concentration.The anti-caries effect of fluoride is due to F_sA HAP and CaF₂Formation, this depend on solution in [F^-] content.

When ■ is higher than 45ppm, calcium fluoride (CaF₂) formed with increased ratio

■[F^-] increase further will not reduce Demineralization further, but increase CaF₂The ratio being formed.

■ have studied the formation of fluor-apatite in enamel with regard to the mechanism ... of fluoride anti-caries effect.

¹⁹The advantage of F MAS-NMR：

(1) optionally detect the local environment of only fluorine atom in sample it is allowed to Direct Recognition [F-] is likely to be present in Possible version in enamel.

(2) detect all of fluorine situation, if：

Crystallization,

Amorphous

Absorption.

(3) measurement is about 0.1% very low concentration of fluorine.

¹⁹F MAS-NMR establishes different fluoride concentrations under the acid condition using dentium nitor mass rather than powder The impact that fluoride-enamel interacts.

For in presence [F^-] in the case of demineralization sample：

(1) determine chemical conversion；

(2) preparation of the apatite that fluorine replaces：^(a)(Ca₁₀CPO₄)₆F_2-x,(F_s-HAP)；With

(3)CaF₂Formation；

■ is in 45ppm [F^-] solution substantially aging partially observable,

■ is in [F^-] higher than 45ppm when, less F_sThe signal that-HAP is formed and CaF increases, and

■ is for [F^-] higher than 136ppm when, most of CaF₂Identified.

Current study show that, the interpolation of fluoride produces the Fs- as dominant chemical only in low dose fluoride compound HAP.

There is abundant evidence that, in the low content of fluoride of following central discovery：

A () saliva can substantially reduce adamantine demineraliting, and

B, () or even under the pH value being typically considered demineraliting, speckle still has the potentiality of remineralization.

Calcium, CaF₂、CaF⁺And phosphate

According to Walton, et.al., " Textbook of Dental Pharmacology and Therapeutics " (Oxford University Press 1994),pp.149and 154:

Pink salt：

Tin ion suppresses the ability that speckle is formed mainly to be studied using stannous fluoride collutory.Often daily 0.1% fluorine Change stannous solution to gargle the accumulation that can substantially reduce antibacterial on tooth.

Stannous ion act through them to mediate with reference to the ability of the lipoteichoic acid on gram-positive bacterium surface. Therefore, the net surface charge of organism is reversed, and therefore decreases absorption on tooth for the cell.Additionally, stannous fluoride Effect in terms of reducing bacterial adhesion power I for the solution be related in aqueous solution the stability of stannous ion and they by specific bacteria The speed absorbing and retaining.Accumulation in antibacterial for the stannum can change their metabolism and other physiochemical properties.

Stannous fluoride：

This also can reduce Dentinal sensitivity.In the solution, its experience spontaneous hydrolysis and oxidation, therefore its with carboxylic first The form of the gel of base cellulose or glycerol mixing is applied.Stannous fluoride serves as enzyme poisonous substance, and can be in odontoblast process Inactivation enzymatic activity in (odontoblastic process).As sodium fluoride, stannous fluoride induces the ore deposit in dentinal tubule Change, it produces calcification barrier in dentin surface.

Christofferson,et.al.,in ACTA ODONTOL.SCAND.1988,46:325-336, report:

" according to showing, the similar fluorination that formed on enamel during the souring soln with high Oil repellent processes enamel The material of calcium is phosphatic calcium fluoride.”

" purpose of this work is to determine growth in waterborne suspension for the pure calcium fluoride and rate of dissolution and controls these The possible mechanism of process, and study by adding in the calcium of hydroxyl phosphorite crystal and/or dissolving and phosphatic system The property of the class calcium fluoride material that fluoride is formed, simulation is as the result of the souring soln Local treatment with high content of fluoride The type of the class calcium fluoride material being formed on enamel.”

" dissolve pure CaF from us containing phosphatic system₂Result can be seen that 1 μm of phosphate to CaF₂'s Rate of dissolution has significant impact.”

" seem more likely as fluoride releasing agent at a slow speed containing phosphatic class calcium fluoride material.”

B.“CaF₂Formation:Cariostatic Properties and Factors of Enhancing the Effect,”Caries Res.,2001；35(Suppl)11:40-41, teaching：

“CaF₂Or class CaF₂The CaF of material/phosphate contamination₂Be dentistry sclerous tissueses Local treatment during dominant response Product.Recently, evidence suggests that CaF2 is not only formed from the teeth outwards, and formed in enamel to a certain extent. CaF₂The Cmin forming required fluoride is not known, and whether can obtain from dental plaque fluid depending on calcium or Only obtained by the dissolving of hard tooth tissue.Additionally, fluoride the surface adsorption of crystal may to be caused CaF2 formed required Local concentration.It has been proposed that CaF₂PH as fluoride controls bin.Rate-controlling factor seemingly phosphate, its Control CaF₂Rate of dissolution at a high ph.Increase fluoride concentration, extend open-assembly time or using the fluorination with low pH Thing solution can increase CaF₂Formed.The CaF being formed in low pH₂Containing less inside phosphate, it has shown that less dissolving Property.For annual local application, fluoride has clinical meaning several times for this.”

" because modern fluoride research starts from the forties in 20th century, the phase therefore between fluorion and hard tooth tissue Interaction is widely studied.Due to the many impurity in hydroxyapatite sample carbonate and magnesium and the examination for the prevention of dental caries A large amount of fluoride concentrations in the middle of agent, pH and composition, the chemical process of the method is complicated.During the pH of speckle circulates, Fluoride can be exchanged with the hydroxyl in apatite, and forms a series of solids with middle composition and crystallographic property, claims For fluorine hydroxyapatite.”

“CaF₂It is to carry out the short time to process main during dentistry sclerous tissueses or may be only with the fluoride reagents of relative enhancement One product (Cruz et.al., Scand.J.Dent.Res., 1992；100:154-158).Certainly, this CaF₂PH control bank play a major role in the dental caries effect of local fluoride.After single local fluoride is processed Several weeks and some months, have detected CaF on hard tooth tissue₂(Caries Res.,1991,25:21-26), and be solution Release unique reasonable manner that this process has dental caries effect.By to the dentium nitor carrying out local fluoride process with KOH Quality sample is processed, lose dental caries effect (et al.,J.Dent.Res.,1990,69:1505- 1507).”

" Review on Fluoride, the with special emphasis on calcium of J.M.ten Cate fluoride mechanisms in caries prevention”,Eur.J.Oral Sci.,1997,105:461-465, religion Lead：

" in order that the effective time processing is longer than the time brushed and subsequent saliva is removed, fluoride needs to deposit Gentle On The Drug Release.Calcium fluoride (or the like) deposit by this way, the surface due to phosphate and/or protein covers, This makes CaF₂Under the conditions of in vivo, the pure form than in inorganic solution is less soluble.Further, since in calcium fluoride ball surface Phosphate groups, when phosphate groups protonate in dental plaque it is assumed that fluoride with pH reduce and discharge.”

" exist in solution (as saliva or dental plaque fluid) low concentration fluoride when, hydroxyapatite may be dissolved in Critical below pH (for hydroxyapatite), but the mineral ion of release can be used as the fluorine hydroxyl phosphorus of fluor-apatite or mixing Lime stone reprecipitation.This mechanism prevents the loss of mineral ion, is placed on apatite crystallite by other that will be enriched in fluorine simultaneously It is above that mineral crystallite provides extra protection.”

" these observations are pointed out, there is the fluoride bank of slow release in denture or mucomembranous surface.Nearest research table Bright, especially in oral mucosa, due to its chemistry and morphological properties and big surface area, it is the reserved bit underestimated of fluoride Point.”

" research shows, a small amount of fluoride in speckle and saliva be enough to beneficially modify demineralization and remineralization balance.So Level should be within a whole day, particularly during the carbohydrate fermentation in speckle effectively.Effective fluorine at a low ph Compound release store system (as shown in for calcium fluoride) will be preferred system.”

Vogel, et al., in " No Calcium-Fluoride-Like Deposits Detected in Plaque shortly after a Sodium Fluoride Mouthrinse”,Caries Res.,2010；44:108-115, report：

" speckle ' class calcium fluoride ' (class CaF being kept by biology/antibacterial calcium fluoride (Ca-F) key₂) and fluoride deposition thing Seemingly in dental plaque fluid the preventing decayed tooth concentration of fluoride source.The purpose of this research is to quantify after sodium fluoride rinses at these The amount of the speckle fluoride retaining in bank.”

" result shows, does not form class CaF in speckle₂Deposit, or, if these deposits have been formed, it Also can lose rapidly.Class CaF of lasting amount can not be formed in speckle₂Deposit, may lead to using conventional fluoride The relatively quick loss of dental plaque fluid fluoride after dentifrice or collutory.”

" based on laboratory [Margolis and Moreno, J.Dent.Res., 1990,69 (Spec.Issue) 606- 613；J.Am.Dent.Assoc.,2000,13:887-889] and clinical observation (commented on by Featherstone, J.American Dent.Assoc.,2000,13:887-889)；"current" model for increasing the anti-caries effect of fluoride (F) medicament is emphasized The importance of the preventing decayed tooth concentration of fluoride is maintained in Oral fluids.”

" seem to come from that the low concentration of oral liquid Ca it is impossible to potentially form more longlasting fluorination doped calcium, this can lead Cause the relatively quick loss with fluoride in speckle after current OTC (over-the-counter) local fluoride medicament.Should note in this respect Meaning, the research that (1) wherein improves this situation using Ca pre-applied produces very in dental plaque fluid and saliva fluoride Big and lasting increase (Vogel, et.al., Caries Res., 2006,40:449-454；Vogel,et.al.,Caries Res.2008(a)421；401-404；and Vogel,et.al.,J.Dent.Res.2008(b)87:466-469)；And (2) Confirmed true using Ca pre-flush before fluoride rinses using the preliminary study (being not disclosed) of the modification of technique described herein Substantial amounts of class CaF can be formed in fact₂Deposit.”

Affinity agent

For the present invention, affinity agent refers to work as and is applied to and is comprised biomembranous oral cavity using processing method of the present invention During surface, stannous fluoride and calcium can be strengthened to the material composition of the described anelasticity comprising biomembranous oral surfaces or material The combination of composition.

Using the anhydrous processing method of the present invention brushing gel unexpected enamel protection and enamel reparation Characteristic brushes the affinity characteristic of the uniqueness shown by gel owing to the present invention.

In order to realize the purpose of the present invention, the preferred affinity agent brushing gel includes polydimethylsiloxane/polymer Various anhydrous Emulsion in nonionic surfactant, its viscosity is at least about 10000cs.

These affinity agent form mucoadhesive gel in the case of there is saliva, and to biomembrane, coated enamel is for it There is affinity, and gradually dissolve in the presence of saliva stream, under at least about 3 pH, stannous fluoride is discharged into dentium nitor On the biomembrane of matter；Thus when applying the processing method of the present invention, producing at least about 2.5 EPF value and at least about 200 respectively ERF value.

In order to realize the purpose of the present invention, affinity agent includes the solvable anhydrous Emulsion of saliva, and it comprises：

Polydimethylsiloxanepolymer polymer in the nonionic surfactant of solid-state, such as United States Patent (USP) 5,032,387； 5,098,711；5,538,667；5,645,841；5,651,959 when described in；There is following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein y=0, and x's and z and between 120 to 150.In preferred embodiments, x=76, y=0 and z= 56.

The nonionic surfactant of liquid has following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and between 125 to 175.In preferred embodiments, x=76, y=25 and z=56.

The combination of solid-state and liquid non-ionic surfactant is also applied for the purpose of the present invention, as long as the emulsion of gained is protected Hold as liquid.All aforementioned reference are incorporated herein by.

In a preferred embodiment of the invention, liquid non-ionic surfactant comprises the continuous phase of anhydrous emulsion.Excellent The liquid non-ionic surfactant of choosing is represented by following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x=76, v=26 and z=56.

Liquid non-ionic surfactant is also preferred with combining of solid-state nonionic surfactant, including have with The solid-state nonionic surfactant of lower structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]-[C₃H₆O]_z-[(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x=76, y=0 and z=56 are suitable.

For the affinity agent in processing method of the present invention the solvable anhydrous Emulsion of preferred saliva include containing liquid non-from Sub- surfactant continuous phase and the anhydrous Emulsion of polydimethylsiloxane (PDMS) discontinuous phase, polydimethylsiloxane (PDMS) range of viscosities of discontinuous phase is about 1500cs to about 2,500,000 cs.It is particularly preferred that anhydrous Emulsion to contain liquid non- The ionic surface active agent continuous phase and viscosity discontinuous phase PDMS between 10000cs to 2,500,000 cs.Can be used as liquid non-from The solid state surface activating agent of sub- surfactant continuous phase auxiliary agent has a detailed description in United States Patent (USP) U.S.5651959.These Liquid and liquid/solid non-tonic surface active agent emulsions form mucoadhesive gel in the presence of saliva.

In a preferred embodiment of the invention, when combining with the anhydrous affinity agent in processing method of the present invention, following Copolymer is used as affinity reinforcing agent.These affinity reinforcing agents include various linear polymers, polycarboxylate, for example：Methyl/ Vinyl/sodium salt of ether/maleic acid and the copolymer of calcium salt, including pictureCommercially available common as MS-955 polymer Polymers, the mixing sodium salt of methyl/vinyl/ether/maleic acid and the copolymer of calcium salt；Its cationic forms cross linked polymer chain Salt bridge.

The chemical constitution of this copolymer is represented by following chemical constitution：

Wherein m is the integer of the molecular weight providing about 60000 to about 1000000 for polymer.

Preferably, the copolymer of maleic anhydride or acid and the ratio of another kind of polymerizable ethylene unsaturated monomers are 1:4 to 4:1, preferably, the molecular weight of methyl vinyl ether (maleic anhydride) is about 30000 to about 1000000.

Sodium salt and the calcium salt of TYLOSE 30000 polymer can also be used, including TYLOSE 30000, ethoxy The sodium salt of cellulose ether, cellulose ether sodium etc. and calcium salt.

Ca from copolymer affinity reinforcing agent⁺⁺Contribution to ERF value is shown in Fig. 5 and Fig. 6 and table 6 and table 7.

Embodiment 1 to 5

Brush gel sample according to the following stannous fluoride being applied in the middle of processing method of the present invention is prepared as described below, and Subsequently test EPF value and/or ERF value, described in the table 2 to 8 of following article：

Embodiment 1 and 2

Embodiment 1

Using overhead type stirrer, by the glycerol of the PEG 400 and 82.768gm of 26.966gm and 48.78gm Add together in 1.64% stannous fluoride glycerite in the rustless steel stainless steel of 1L.With low speed while being heated to 80 DEG C Start to stir.Then add the L-1220/250 ten thousand cs PDMS's (10%) of 2.84gm while stirring Affinity agent, stirs 15 minutes.The speed of overhead type stirrer is improved to medium, and adds 1.88gm's while stirring Gantrez MS-955 affinity reinforcing agent, stirs 5 minutes.Be subsequently adding 1.42gm Crodasinic L, 0.18gm three Chlorine sucrose and the saccharin insoluble of 0.56gm, continue stirring 10 minutes.Add the TEGO glycine betaine CKD of 1.42gm, and stir 5 points Clock.Add micronized anhydrous 2-Butenedioic acid (E)-, calcium salt 2.84gm, stir 5 minutes, be subsequently adding micronized AMSP 0.612gm, continues stirring 5 minutes.

Add the Sipernat 22S of 28.3gm in the way of multiple interpolation, stir 2 minutes between each addition.When After Sipernat 22S is all added, continue stirring 15 minutes, be subsequently adding the brisbane pennyroyal (Vanillamint) of 1.32gm With the Multisensate spice of 0.114gm, continue stirring 5 minutes.Remove agitator, by gel-filled in distribution pipe.When During as brushing gel, user may feel that pleasant, salubrious mouthfeel and considerably less metallic taste.

Embodiment 2

Using the method described in embodiment 1, prepare the second brushing without Gantrez MS-955 affinity reinforcing agent Gel.

Embodiment 3 to 5

Brush gel using three kinds of stannous fluoride that the method for above-described embodiment 1 and 2 is prepared for processing method of the present invention Preparation, as described below.Gel preparation is brushed to these and carries out testing in vitro.Result is reported in table 5 to 7 and Fig. 4 to Fig. 6 of accompanying drawing In.

Embodiment 3

Gel brushed by stannous fluoride

Embodiment 4

Gel brushed by stannous fluoride

Embodiment 5

Gel brushed by stannous fluoride

The testing in vitro of the processing method of the embodiment of the present invention：

The external test of EPF value is attributable to apply various fluorides, including：It is administered to the mankind's dentium nitor standing acid test Toothpaste in matter and experimental brushing gel.

The monograph of the OTC (over-the-counter) preventing decayed tooth medicine being used with regard to the mankind according to FDA carries out following research.This research is according to FDA's GLP is carried out.

The purpose of following in vitro study：Determine the human dental to the brushing product treatment using various fluoride for the acid test The impact of enamel.Various fluorine used by the enamel sample that the effect of acid test passes through measurement various fluorides brushing product treatment The resistance that compound is tested to acid before and after brushing product treatment to determine.

Tooth prepares：

Three healthy mankind's molars are placed in red boxing cake wax so that only enamel surface exposes.Prepare 12 groups of (every group three) teeth are used for studying.All samples are all cleaned with pumice and buff wheel and polish, to remove Any deposit or spot.

Lactic acid tests the preparation of buffer solution：

With the 88.5% of two moles of 203.58g of about 500ml distilled water diluting pure lactic acid.It is added thereto to NaOH molten Liquid, this solution is that the NaOH dissolving 84g in about 600ml distilled water forms.Then cumulative volume is adjusted to 2000ml.This is 1.0M Lactic acid tests buffer solution.

Prepare another kind of lactic acid solution by 2 molar lactic acid being diluted to 2000ml with distilled water.By lactic acid and hydrogen-oxygen The solution changing sodium is placed in 4000ml beaker, and pH electrode is placed in solution.Using 1.0M lactic acid solution by buffer solution PH regulator is to 4.5.In order to obtain 0.1 working concentration (for all decalcifications), with distilled water, 1.0M buffer is diluted 10 times.

Deprotection：

Before each is used, eliminate by the antilysis protection of previously processed provided any residual.By In the 0.1M lactic acid salt buffer solution of above-mentioned preparation, etching tooth two hours is completing the deprotection of these samples.In the deprotection phase Between, three samples in each disk stir (450rpm) at room temperature in the lactic acid salt buffer solution of about 50ml.In deprotection Fully rinse tooth with distilled water immediately afterwards.

Before processing etches：

Set of teeth and lactic acid salt buffer solution using preheating (37 DEG C) are tested.By the set of teeth of deprotection using molten Melt red boxing wax to be arranged on the acrylic acid rod of 1/4 inch diameter.Processed using multiple agitator and etched.To own Slurry and solution are preheated to 37 DEG C.Actual treatment is carried out on the table top have preheated solution with being etched in.Plastic sample vessel (120ml) it is used for etching process.Get out 1/4 inch of hole to accommodate the plastic bar being provided with set of teeth in each container cover. The 40ml part of 0.1M lactic acid buffer is placed in each container together with 1 inch of magnetic stirring bar.First set of teeth Bar is pushed through the hole in lid, is placed in the first container and adjusts so that all enamel surfaces immerse buffer solution In.Then container is placed on the first magnetic stirring apparatuss and starts to stir.Now start intervalometer.With the interval of 30 seconds, with phase Same mode starts other set of teeth.After being exposed to lactic acid salt buffer solution 15 minutes, stop first group, and Jiang Gai and Ya Tooth group is taken out from container immediately and is placed in distillation water pond to terminate etching.Other groups are spaced with 30 seconds with identical order Similarly remove, and retain lactic acid salt buffer solution and analyze for phosphorus.Set of teeth is put back in 37 DEG C of water-baths to prepare to be fluorinated Thing process step.

Process：

Processed using the slurry that fluoride brushes product.Slurry is preheated by 1 part of fluoride brushing product and 3 parts (37 DEG C) distilled water (9g：27ml) form.Every kind of slurry mixes lucky one minute after addition of water.Slurry does not carry out standard in advance Standby.They are not centrifuged.All set of teeth process (every group corresponds to a kind of fluoride and brush product) simultaneously.Except Outside replacing acid with slurry, this processing procedure is similar to etching process.The preheating fluoride of 30ml is scrubbed slurry and adds first Set of teeth, tooth is immersed in slurry, container is placed on the first agitator.Start agitator and intervalometer.Between 90 seconds Every (to allow mixing time), start other set of teeth in an identical manner.At the end of five minutes are processed, stop first group, Take out set of teeth and fully rinsed with distilled water.Other set of teeth were removed with the interval of 90 seconds and fully rinses.Discard process fluorine Compound scrubs slurry.

After process：

Then carry out the second subacid exposure by etching identical method with before processing, and it is molten to retain lactic acid salt buffer again Liquid is used for phosphorus and analyzes.Analyze and process solution after front and process using Klett-Summerson electrophotometer.

Replicate analysis：

Repeat extra number of times by set of teeth deprotection and by this process so that every kind of fluoride brushes product in each tooth Processed in tooth group and detected.This process design is Latin square design, so as one man not following a kind of the another of process Plant and process.

The calculating that dental enamel dissolution degree reduces：

The difference of the amount of phosphorus that the percentage ratio that dental enamel dissolution degree reduces is calculated as in front acid solution and rear acid solution is removed The amount of the phosphorus in acid solution be multiplied by 100 in the past.

Treatment group：

A. placebo (deionized water)

B. positive control 1, has stannous fluoride containing 1100ppm fluoridePRO-Toothpaste

C. positive control 2, have sodium fluoride containing 5000ppm fluoride5000 toothpaste

D. using test gel in processing method of the present invention, it has described in following article embodiment 1 containing 970ppm fluorination The stannous fluoride of thing composition.

Statistical analysiss：

Using Sigma Stat (3.1) software, carry out the statistical of individual meansigma methodss using the one-way analysises of Tobin's mean variance model Analysis.Because ANOVA indicates significant difference, by Student Newman-Keuls (SNK) analysis of experiments individuality meansigma methodss.

Result and discussion：

Deionized water negative control is less effective in terms of reducing dental enamel dissolution degree.Fluorine-containing cationic comparison and test are solidifying Glue is significantly more more effective than deionized water negative control.ClinproToothpaste is notable more more effective than negative control.Using survey The processing method of the present invention of examination gel is significantly more effective than other two kinds of positive controls in terms of reducing dental enamel dissolution degree.

Result is shown in table 2 below：

Table 2

Dental enamel solubility reduces

The summary of results

* meansigma methodss ± SEM (N=12)

* brushes enamel protection factor (EPF) value of product to measure every kind of fluoride, by dental enamel dissolution degree Reduce the content of fluoride (ppm) divided by the brushing product tested for the percentage ratio.Institute's total is multiplied by 100.

Fig. 1 referring to accompanying drawing.

Due to applying various toothpastes with fluoride at the initial stage injury of teeth in bovine-enamel and applying present invention process side The brushing gel of method and the external test of ERF value that leads to.

According to FDA with regard to people with the monograph of OTC (over-the-counter) class anticariogenic agent product, the GLP according to FDA is carried out Hereinafter study.

Carry out the purpose of following in vitro study：Determine and brush product and disposal methods of the present invention with various fluoride Cattle front tooth initial stage injury of teeth in Absorption of Fluoride.

In addition to being formed using the solution comprising 0.1M lactic acid and 0.2% Carbomer (Carbopol) 907 and damaging, this survey Examination program and FDA preventing decayed tooth specially in be designated program 40 program identical, wherein HAP (hydroxyl phosphorus under 5.0 pH value for the solution Lime stone) saturation.

Fluoride after analyzing enamel before processing and enamel process and calcium content determine Absorption of Fluoride, with Determine the change of the enamel fluoride owing to the brushing product treatment using fluoride.

Program：

Select the cattle front tooth of undamaged center upper portion and remove the soft tissue of all adhesions.By using hollow diamond drill Head perpendicular cuts lip surface to prepare the enamel core of a diameter of 3mm from each tooth.This is carried out under water to prevent sample mistake Heat.Using methyl methacrylate, each sample is embedded the end of perspex bar (1/4 " diameter × 2 " length).Cut away The acrylic acid of amount, to expose enamel surface.Enamel specimen is first used wet/dry paper of granularity 600 and then is used ultra tiny gamma again Aluminium oxide polishes.The sample obtaining is the enamel disk of 3mm, is covered with acrylic acid in addition to exposed surface.Prepare every group 12 samples.

Then to etch each enamel specimen within 15 seconds in the 1M perchloric acid by immersion 0.5ml.In the whole etching phase Between, continuous stirring etching solution.Then adjusting buffer solution (TISAB) (fluorion probe's buffer) with total ionic strength will be every The Sample Buffer of kind of solution to pH 5.2 (0.25ml sample, the 1N NaOH of TISAB and 0.25ml of 0.5ml), by with similar The standard curve (TISAB of the std+1ml of 1ml) of preparation compares the content of fluoride to determine solution.In order to calculate each Depth in use, by taking 50 μ l and the calcium of etching solution being determined by Atomic Absorption (0.05ml qs to 5ml) analysis calcium Content.These data are the intrinsic content of fluoride of each sample of before processing.

Again as described above sample is ground and polishes.By immersing lactic acid/0.2% of 0.1M at room temperature 24 hours in Carbopol 907 solution, each enamel specimen forms initial damage.Then these samples are distilled Water fully rinses and is stored in wet environment until using.

Slurry using the brushing product of various fluoride is processed.This slurry is produced by the brushing of 1 part of fluoride Product and 3 parts of distilled water (9g：27ml) form.Every kind of slurry mixes lucky one minute after addition of water.Slurry is not carried out in advance Prepare.They are not centrifuged.Then every group of 12 samples are immersed in its slurry specified of 25ml, persistently stir Mix (350rpm) 30 minutes.After process, use distilled water flushing sample.Then remove one layer of enamel from each sample, and such as Upper described analysis fluoride and calcium (i.e. etching in 15 seconds).Then deduct before processing fluorine fluoride number after the process of each sample Compound (intrinsic) content, to determine the change of the enamel fluoride of last process.

Statistical analysiss：

Report all initial datas of enamel Absorption of Fluoride (EFU) value of single sample.In addition, calculating every group Average SD (standard deviation) and SEM (scanning electron micrograph).Using Sigma Stat software (3.1), by one-way analysises Tobin's mean variance model carries out statistical analysiss.Due to showing significant difference, divided by Student Newman Keuls (SNK) method of testing The individual meansigma methodss of analysis.

Test product：

The fluorine-containing brushing product coding of test is as follows：

1. placebo (deionized water)

2. positive control 1, has stannous fluoride containing 1100ppm fluoridePRO-

3. positive control 2, have sodium fluoride containing 5000ppm fluoride5000

Using test gel in processing method of the present invention, it has fluoride containing 970ppm described in following article embodiment 1 The stannous fluoride of composition.

Result：

Result is shown in table 3 below：

Table 3

The change of the enamel content of fluoride of initial damage

* meansigma methodss ± SEM (N=12)

* value 15.32 and 15.28 does not have significant difference

The enamel that * * brushes product to measure every kind of fluoride repairs coefficient (ERF) value, will be dense for enamel fluoride The incrementss of degree brush the content of fluoride of product divided by fluoride.Institute's total is multiplied by 100.

Fig. 2 referring to accompanying drawing.

Due to applying the various toothpastes with fluoride of processing method of the present invention at the initial stage injury of teeth in human enamel The external test of the ERF value leading to brushing gel, the enamel fluoride scheme according to the reported result of above-mentioned table 3 is entered OK.In the research of this Absorption of Fluoride, some fluoride of test brushes those knots that product is different from report in upper table 3 Really.

Table 4

The change of the enamel content of fluoride of initial damage

* meansigma methodss ± SEM (N=12)

The enamel that * brushes product to measure every kind of fluoride repairs coefficient (ERF) value, by (after process) dentium nitor The average increase of matter fluoride concentration brushes the content of fluoride of product divided by the fluoride tested.Institute's total is multiplied by 100.

Fig. 3 referring to accompanying drawing.

Table 5

The change of the enamel content of fluoride of initial damage

* meansigma methodss ± SEM (N=12)

Fig. 4 referring to accompanying drawing.

Table 6

The change of the enamel content of fluoride of initial damage

* meansigma methodss ± SEM (N=12)

Fig. 5 referring to accompanying drawing.

Table 7

The change of the enamel content of fluoride of initial damage

* meansigma methodss ± SEM (N=12)

Fig. 6 referring to accompanying drawing.

Table 8

The summary of gel ERF data brushed by stannous fluoride, based on the method for the present invention using various brushing gel components, As described in Fig. 2 to Fig. 6 of table 3 to 7 and accompanying drawing

The illustrative example of gel is brushed used in processing method of the present invention

Table 9

Table 10

For " excessive risk " patient using the processing method of the present invention brushing gel

Embodiment 15

5 liters of Ross/Olsa vacuum mixers with internal homogenizer are heated to 80 DEG C, add in container simultaneously 1.64% stannous fluoride/the glycerol of the PEG 400, the anhydrous glycerol of 2069.2gm and 1219.5gm of 647.15gm.Start with low Speed carries out grappling stirring, and continues 7 minutes.Add 71gm's[Plurocare L-1220 (90%)] and 2,500,000 cs polydimethylsiloxane (10%), homogenizer speed is adjusted to 2500rpm, continues 15 minutes.By anchor Formula agitator rises to medium speed, and adds the Gantrez MS-955 of 47gm under agitation, and homogenizing 5 minutes.Add The Crodasinic L of 35.5gm, continues stirring 5 minutes.Add the TEGO glycine betaine CKD of 35.5gm, continue stirring 5 minutes.Plus Enter the anhydrous 2-Butenedioic acid (E)-, calcium salt 71gm of micronization (20 microns of D50), stir 5 minutes.Add micronization (20 microns) anhydrous phosphoric acid two Hydrogen sodium 15.3gm, stirs 5 minutes.Add the Sident 22S of 707.5gm in the way of multiple interpolation, between each addition between Every 2 minutes, add until whole.Continue stirring 15 minutes.

Add brisbane pennyroyal (Vanillamint P) flavoring agent of 33gm and the Herba Pelargonii Graveolentis extract of 2.85gm, continue stirring 5 Minute.Container was cooled to ambient temperature in 15 minutes.Content is assigned in pipe for using.In extrusion distribution, Brush the taste that gel shows pleasant, there is no stannous fluoride pleasant impression.Stannous fluoride stability test is carried out to this product.

The EPF value set up by vitro tests and the discussion of ERF value

The commercial toothpastes using various content of fluoride reported with such as table 2 to 7, Fig. 1 to Fig. 6 and summary sheet 8 Method is compared, and shows the substantive improvement of EPF value and ERF value using the processing method of the present invention that gel brushed by stannous fluoride.

For example, the use reported in table 3 and in figure 2PRO-And ClinproToothpaste ERF value is respectively 170 and 65, and by comparison, the ERF value brushing the processing method of the present invention of gel using stannous fluoride is 300. The use of report in Fig. 6 of table 7 and accompanying drawingPRO-The ERF value of toothpaste is respectively 210, phase therewith The ERF value brushing the processing method of the present invention of gel using stannous fluoride is 1070 to ratio.

Compared with commercial toothpastes, ERF value increases by 2 times and 5 times respectively, and this shows the processing method of the present invention in fluoride Absorb the major advantage with enamel hardening aspect.This advantage in terms of enamel hardening effect is for child and following Patient is particularly critical：Rampant caries tooth, crown dental caries, treatment of cancer, mucositis treatments, immunodeficiency treatment, bone marrow transplantation etc..

The mechanism of action of processing method of the present invention

Enamel with regard to being reported using such as the processing method of the present invention of the preparation in embodiment 1 to 5 is protected and/or tooth Enamel is repaired in (EPF and/or ERF) data, such as table 2 to 8 and Fig. 1 to 6 and is described in detail.It shows, stannous fluoride and calcium are to being present in Biomembranous affinity on enamel surface is tied from bidentate calcium in the case of there is stannous fluoride by this processing method Conjunction is changed into monodentate calcium and combines and strengthened.In the case of there is stannous fluoride, this transformation that calcium combines achieves It is effectively combined site configuration (binding site configuration).See：

Dudey and Lim,J.Phys.Chem B,2004,108:4546.

Vogel,et.al.,Caries Res.,2010,94:108-115.

Rolla and Bowen,Scand.J.Dent.Res.,1977；85:149-151.

Rose,et.al.,J.Dent.Res.,1993；72:78-84.

Separately refer to:

Turner,et.al.,Ceramics,Silikaty 57(1):1-6(2013)

Mohammed,et.al.,Caries Res.,47:421-428(2013)

Calcium bridge, fluoride combines

Using the processing method of the present invention, chelate from bidentate depositing the calcium in the case of fluoride, being combined with biomembrane Thing is transformed into monodentate chelate, release calcium cation with fluoride, CaF+ to combination so that calcium-binding capacity doubles.

In the processing method of the present invention, brush the notable fall that the stable fluoride in gel creates calcium binding affinity Almost the doubling of low and calcium-binding capacity.It is bidentate not depositing the calcium in the case of fluoride, being combined with biomembrane and combining 's.The stable fluoride brushed in gel at these is competed with biomembrane, leads to calcium and biomembranous combination to become monodentate.This So that being attached to biomembranous calcium and the quantity of CaF+ almost doubles.It is scavenged into the result in saliva as fluoride, by calcium The release being bridged to the fluoride combine in biological membrane fluid by always with the corresponding release of calcium, this so strengthen fluoride Dental caries effect, shown in the in vitro tests as described in table 2 to table 7 and Fig. 1 to Fig. 6.

It is present in the brushing stable fluoride of at least some of gel for processing method of the present invention and calcium ion (source From the various calcium salts in the present invention and/or be present in calcium in copolymer affinity reinforcing agent, such asMS-955) In conjunction with.These calcium ions are attached on the biomembrane being associated with enamel again.

After speckle is exposed to sucrose (it passes through neutralization and removes some anionic groups), pH reduces, thus at this A little position release calcium that partly can give play to maximum effect and fluoride are (as CaF⁺).

Effectiveness using the processing method of the present invention brushing gel depends on three factors：

(1) preparation is to biomembranous affinity,

(2) as CaF⁺The stannous fluoride in source,

(3) it is trapped in the fluoride of form on biomembrane, it allows CaF⁺Plasma diffusing W,Mo is in hydroxyapatite.

Stannous fluoride makes calcium binding affinity significantly reduce, and the intimate multiplication along with calcium-binding capacity.Do not depositing In the case of fluoride, the bivalent cation being combined with dental plaque is bidentate.Fluoride is competing with macromole anionic group Strive, lead to combination to become monodentate.Along with the release of calcium, it strengthens fluoride for the release of the fluoride being formed by calcium bridge joint Dental caries act on.

Need there is CaF⁺With realize using brush gel component processing method of the present invention needed for enamel protection and Repair (EPF and ERF) effect.

The summary of effect in microorganism fluoride combines for the cation bridge joint

In the processing method of the present invention, fluorine combines and calcium binding affinity is significantly reduced, and makes calcium combine energy Power doubles.This shows that calcium combines and is changed into monodentate from bidentate.This transformation from bidentate to monodentate is that fluorine replaces anionic group work Result for one of calcium coordination.

The anionic group being no longer combined with calcium is dissociated and can be combined with CaF+ ion pair, leads to calcium-binding capacity to double. The release being bridged to the fluorine combine in dental plaque fluid by calcium can be with the release of calcium, and the dental caries strengthening fluoride are made by calcium With.

CaF⁺Absorbed and be reported as by hydroxyapatite EPF and ERF of the vitro data for processing method of the present invention. In Fig. 2 to Fig. 6 of table 3 to table 8 and accompanying drawing, the ERF value of report shows, during the remineralization processing method of the present invention, CaF⁺Part is incorporated in hydroxyapatite lattice.

Using the processing method of the present invention brushing gel be enamel protection and enamel reparation set up new oral cavity and protects Reason standard, significantly reduces the contact with the various fluoride varnishs, gel and toothpaste of high content of fluoride simultaneously.

Claims

1. enamel processing method, it uses substantially anhydrous enamel protection and enamel reparation to brush gel, described brushing Gel contains stannous fluoride and calcium in affinity agent, wherein：

（a）In the case of there is stannous fluoride, by calcium from bidentate combine to monodentate combine transformation, described stannous fluoride and Calcium is strengthened to the biomembranous affinity being present on enamel；With

（b）Exist biomembranous in the case of, by being applied to described brushing gel period on enamel surface, respectively Realize at least about 2.5 EPF value and at least about 200 ERF value.

2. enamel processing method according to claim 1, wherein said affinity agent be selected from solid-state and liquid non-from Sub- poloxamer and combinations thereof.

3. enamel processing method according to claim 1, some in wherein said stannous fluoride are with CaF⁺Presented in.

4. enamel processing method according to claim 2, wherein said affinity agent contains linear polymerization polycarboxylate parent With property reinforcing agent.

5. according to claim 4 using brush gel enamel processing method, in affinity agent contain stannous fluoride and Calcium, described affinity agent includes the Emulsion of the polydimethylsiloxanepolymer polymer that viscosity is about 10000 cs to about 2,500,000 cs, its work For the discontinuous phase in nonionic liquid surfactant continuous phase.

6., according to claim 5 using the enamel processing method brushing gel, wherein it is suitable for described brushing gel Nonionic liquid poloxamer surfactants are represented by following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]- [C₃H₆O]_z- [(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and be 125 to 175.

7. enamel processing method according to claim 4, is wherein suitable for the described nonionic liquid table brushing gel Face activating agent is represented by following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]- [C₃H₆O]_z- [(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x=76, y=25 and z=56.

8. enamel processing method according to claim 1, its use described brushing gel contain unreacted calcium and Phosphate component.

9. enamel processing method, it uses substantially anhydrous enamel protection and enamel reparation to brush gel, described brushing Gel contains stannous fluoride and calcium in affinity agent, and it is the poly- of about 10000 cs to about 2,500,000 cs that described affinity agent includes viscosity The Emulsion of dimethylsiloxane polymer, it is as discontinuous in nonionic solid-state poloxamer surfactants continuous phase Phase, described affinity agent contains linear polymerization polycarboxylate affinity reinforcing agent.

10., according to claim 9 using the enamel processing method brushing gel, wherein it is suitable for described brushing gel Nonionic solid-state poloxamer surfactants are represented by following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]- [C₃H₆O]_z- [(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and be 120 to 150.

11., according to claim 9 using the enamel processing method brushing gel, are wherein suitable for described brushing gel Nonionic solid-state poloxamer surfactants are represented by following structural formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]- [C₃H₆O]_z- [(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x=76, y=0 and z=56.

12. according to claim 9 using the enamel processing method brushing gel, and wherein said brushing gel contains not anti- The calcium answered and phosphate component.

13. according to claim 6 using the enamel processing method brushing gel, wherein said nonionic surfactant For liquid surfactant, it is selected from the group of the liquid surfactant with following general structural Formula：

HO[(C₂H₄O)_x/(C₃H₆O)_y]- [C₃H₆O]_z- [(C₂H₄O)_x/(C₃H₆O)_y]H

Wherein x, y and z and be 125 to 175.

14. enamel processing methods, it uses substantially anhydrous enamel protection and enamel reparation to brush gel, and its feature exists In in the case of there is stannous fluoride, the monodentate of calcium-bidentate combines；It contains：Stannous fluoride, calcium and phosphate component, parent Mediating recipe Emulsion, described affinity agent Emulsion comprises as the liquid nonionic poloxamer surfactants of continuous phase and as non- The polydimethylsiloxanepolymer polymer of continuous phase；It has at least about 2.5 EPF value and at least about 200 ERF value.

15. according to claim 6 using the enamel processing method brushing gel, and wherein said polydimethylsiloxane gathers Compound discontinuous phase constitutes up to the 40% of described Emulsion.

16. enamel processing methods, it uses substantially anhydrous enamel protection and enamel reparation to brush gel, described brush Apply gel and contain stable stannous fluoride and calcium in the affinity agent to the enamel that biomembrane covers with affinity, wherein：

（a）In the case of there is stable stannous fluoride, combine to monodentate by affinity reinforcing agent with by calcium from bidentate In conjunction with transformation, described stannous fluoride and calcium are strengthened to described biomembranous affinity；With

（b）Described stannous fluoride is being converted into CaF when described affinity agent discharges⁺Part, it realizes at least about 2.5 respectively EPF value and at least about 200 ERF value.

17. according to claim 1 using the enamel processing method brushing gel, wherein from the release of described affinity agent When, described stannous fluoride includes the CaF when described calcium monodentate is bound to the described biomembrane being present on enamel⁺Part.

18. according to claim 1 using the enamel processing method brushing gel, and wherein said brushing gel is being applied to There is pH value during biomembranous enamel and be at least about 3.

19. according to claim 4 using the enamel processing method brushing gel, and the content of wherein said affinity agent is about 0.5% to about 5%（Weight）, the content of described affinity reinforcing agent is about 0.1% to about 3%（Weight）.

20. according to claim 1 using the enamel processing method brushing gel, the model of wherein said EPF value and ERF value Enclose is about 380 to about 1070.

21. according to claim 1 using the enamel processing method brushing gel, and wherein said calcium is selected from following calcium and becomes Divide formed group：2-Butenedioic acid (E)-, calcium salt, calcium sulfate, calcium gluconate, the mixing sodium salt of methyl/vinyl/ether/maleic acid and calcium The copolymer of salt, and combinations thereof.

22. according to claim 4 using the enamel processing method brushing gel, and wherein said affinity reinforcing agent has Following structural formula：

Wherein m is the integer providing weight between about 60000 to about 1000000.

23. according to claim 1 using brush gel enamel processing method, wherein the total content of calcium about 0.5 to Between about 5.0.

The enamel processing method of 24. " excessive risk " patients, described patient includes immune deficient patients, cancer therapy patients, sugar Urine patient, COP patient, mucositiss patient and cardiovascular patient；Methods described includes applying enamel to described patient Gel is brushed in protection and enamel reparation, and described brushing gel comprises：Stannous fluoride, calcium and affine agent emulsion, described affinity agent Emulsion contains the nonionic surfactant as continuous phase and the polydimethylsiloxanepolymer polymer as discontinuous phase；Described Method also includes applying described gel with certain frequency, and described frequency be enough to realize at least about 2.5 EPF value and at least about respectively 200 ERF value.

The enamel processing method of 25. " excessive risk " patients, protects and dentium nitor including applying enamel as claimed in claim 1 Gel is brushed in matter reparation, and its frequency of administration be enough to realize at least about 2.5 EPF value and at least about 200 ERF value respectively.

The enamel processing method of 26. " excessive risk " according to claim 1 patients, wherein said enamel protection and tooth The time of application that gel is brushed in enamel reparation is up to two minutes, then spues；Its frequency of administration be enough to realize at least about 2.5 respectively EPF value and at least about 200 ERF value.

The enamel processing method of 27. " excessive risk " according to claim 1 patients, wherein said enamel protection and tooth Gel is brushed in enamel reparation:(a) during the day between be administered as needed；And (b) go to bed at night before apply；From And realize at least about 2.5 EPF value and at least about 200 ERF value respectively.