CN109789075A - For promoting the oral care composition of gums healthy - Google Patents

Abstract

The present invention provides the oral care composition comprising antifibrinolysis agent (for example, tranexamic acid) and stannous ion source for promoting the gums healthy of consumer.

Description

For promoting the oral care composition of gums healthy

Technical field

What it is the present invention relates to the gums healthy for promoting consumer includes stannous ion source and antifibrinolysis agent Oral care composition.Specifically, such oral care composition can be used for improving gums wound healing and improve consumer The reduction of bacterial activity in oral cavity.

Background technique

Gum disease such as gingivitis and/or periodontitis cause acute and chronic gingivitis in the oral cavity." gingivitis " It is the slighter form of the disease.The symptom of gingivitis may include: gingiva bleeding gingival hemorrhage；With rubescent, swelling or gum edema.Such as Fruit is handled not in time, and gingivitis can develop into " periodontitis ".For periodontitis, gum falls off from tooth and forms referred to as " tooth The space in all chamber holes ", can be by pathogenic bacterial infection.Bacterium is present on root surface as biomembrane.Bacterium in biomembrane Gums and following alveolar bone may be attacked, which is used to support tooth.These attacks may be to soft group of supports tooth It knits and causes serious harm with bone.In the later stage (i.e. " severe periodontitis ") of gum disease, in fact it could happen that more serious tooth The problem of loose compact and final absence of tooth.

Some commercially available oral care compositions are mainly used for alleviating early stage (the i.e. gums of gum disease It is scorching) one or more symptoms comprising: alleviate rubescent, swelling or gum edema；And/or dry bleeding gums.In general, these Composition proposes such as " gingiva care ", " oral care ", " oral health ", " dental care " or " dental health " to consumer Beneficial effect.The example of such composition be "Total " toothpaste, they, which claim, " helps to reduce gum disease First stage ", be defined as " gingivitis or bleeding gums " (referring to http://www.colgatetotal.com/ total-benefits/whole-mouth-health/gingivitis-control).It is commercially available in order to help distinguish between Oral care composition relative to beneficial effects of the present invention, the present inventor is herein by these commercially available oral cavities The above-mentioned beneficial effect of care composition is referred to as " gingiva care ".This is because these commercially available oral care combinations Object is mainly configured to nursing gum and associated with early stage (i.e. the gingivitis) of the gum disease symptom of alleviation (such as tooth Oulorrhagia；And/or rubescent, swelling or gum edema).

It is as used herein wider term and purport however, it is necessary to provide totality " gums healthy " beneficial effect Including at least some of above-mentioned gingiva care beneficial effect, and is providing additional antibacterial benefit to mitigate bacterium Adverse effect, because it is related to gum disease (including gingivitis, periodontitis or both).

There are at least one of several disadvantages for above-mentioned conventional method.Firstly, these commercially available oral care groups Closing object can promote gingiva care, but they are also much not enough to promote gums healthy.In fact, in addition to gingiva care is beneficial to effect Except fruit (for example, antihaemorrhagics and/or anti-swelling), these commercially available oral care compositions generally can not provide any Significant antibacterial effect.This is a problem, because if the bacterium in biomembrane is uncontrolled, so they may then increase Add the size in periodontal cavity hole, so as to cause periodontitis.Secondly, gums healthy may be related to whole health.In other words, Personal gums healthy can be the index of the whole health of the people.Studies have shown that occurring as overall gums healthy reduces The illness (such as heart disease and stroke, diabetes, nephrosis, premature labor and/or osteoporosis) of these potential threat to life Any one of the risk of (or a variety of) may will increase (referring to United States Patent (USP) 6,846,478；Doyle,M.J.；It is special with the U.S. Benefit 8,283,135；Doyle,M.J.).Therefore, it is intended that improving whole gums healthy, rather than just gingiva care, to ensure Preferably entirety health.

Other commercially available oral care compositions can contain antibacterial agent, which is intended to control in biomembrane carefully The growth of bacterium.Some oral cavity compositions can also contain tranexamic acid and fluoride source.Tranexamic acid has been described as can be used for tooth The antihaemorrhagics agent of gum wound healing.It also describes and inhibits gums inflammation and/or play the role of anti-swelling agent (referring to United States Patent (USP) 4,272,513；Gaffar,A.；With 4,272,512；Gaffar,A.).Fluoride is sufficiently proved to prevent and control dental caries Tooth.One of oral care composition containing tranexamic acid is the disadvantage is that tranexamic acid may become the unstable and mistake in aging Go its activity.In addition, unstable tranexamic acid may make oral care composition fade, turn yellow it to dark-brown, This is undesirable for consumer.The previous oral care composition for having described unstability and the problem that fades has been used The tranexamic acid of 1.5% to 2% higher level is prepared (referring to United States Patent (USP) 4,272,513；Gaffar, A. and 4,272, 512；Embodiment in Gaffar, A.).According to these bibliography, higher level is needed for wound healing and other to have Beneficial effect provides enough tranexamic acid effects.In order to overcome these problems, it is attached that addition has been sought help from these previous trials The component added, such as TiO₂, folic acid or flavouring mixture be (for example, gaultherolin, menthol, eugenol and eucalyptus Brain) to prevent fading without the stability and activity for significantly reducing tranexamic acid in above-mentioned storage.However, there is a continuing need for Simplify formula and procedure of processing to provide high performance-price ratio and effective toothpaste and other oral care formulations.

The antibacterial agent that can be used for these other commercially available oral care compositions may include such as: citric acid Zinc (such as Darlie^TMExpert toothpaste), IPMP (such as Lion^TMSystema toothpaste) and hexadecylpyridinium chloride (CPC).Regrettably, these antibacterial agents may have the permeability of difference to biomembrane.As a result, these antibacterial agents can be can be with Simply chemical degradation before the bacterial interactions of biomembrane depths.Alternatively, antibacterial agent, which can express, to show biomembrane Write slow infiltration rate.As a result, these antibacterial agents there may be inefficient infiltration rate in biomembrane, and need longer Time engage and kill bacterium.It is believed that one or more of these disadvantages have these oral care compositions less Effect promotes gums healthy, especially because it is related to reducing bacterial activity.

A solution be the antibacterial agent of higher amount is added with adapt to their degradations and/or suboptimum in biomembrane or Inefficient infiltration rate.However, in view of the relatively high minimum inhibitory concentration of these antibacterial agents (" MIC ") (data are not shown), oral cavity Amount needed for these antibacterial agents provide effect in care product may be unreasonable height.MIC is the minimum of every milliliter of antibacterial agent Concentration (in terms of microgram), is not observed bacterial growth under the concentration.Lower than MIC concentration under, antibacterial agent to kill or The growth and breeding for inhibiting bacterium are invalid.Higher than MIC concentration under, antibacterial agent to kill or inhibit bacterium growth and Breeding is effective.

This may be in turn unfavorable for several aspects, including since maximum upper safety limit or use are continuously increased Amount these antibacterial agents cost limitation and the limitation to oral care product effect, and/or may with higher level these The associated adverse side effect of antibacterial agent.In brief, since these antibacterial agents enter chemical degradation in biomembrane and/or secondary Excellent or inefficient permeability, it has been required to which improved oral care composition is to promote gums healthy beneficial effect.If this new Oral care composition in biomembrane have improved antibacterial action, then be ideal.

Accordingly, it is desirable to provide a kind of oral care composition, which provides the consumer with gums healthy Beneficial effect at least provides associated gums healthy beneficial effect (example preferably than those of commercially available composition Such as, gums wound healing and antibacterial benefit).

Summary of the invention

The present invention attempts to be based at least partially on following be surprisingly found that solve this needs: oral care combination Antifibrinolysis agent (such as tranexamic acid) and the combination of stannous ion source promote to include at least gums wound healing in object With the gums healthy beneficial effect of antibacterial benefit.Specifically, oral care composition includes for gums wound healing Tranexamic acid and stannous ion source as antibacterial agent, to fight the adverse effect of bacterial activity in oral cavity.

It is one advantage of the present invention that " the preferably infiltration of depth biomembrane and/or killing bacteria ".For this purpose, further making us frightened It finds with being surprised, when being applied in combination with tranexamic acid, penetration depth and/or infiltration speed that stannous ion enters biomembrane can be increased Rate.In brief, the synergistic combination of the tranexamic acid in oral care composition and stannous ion source, which may make, realizes that gum is strong The improvement of health beneficial effect.In addition, improved gums healthy can be provided using oral care composition of the invention for consumer Beneficial effect.

Yet another advantage of the present invention is that provide the oral care composition for promoting gums healthy because it be related to The associated symptomatology of gingivitis, periodontitis or both.Another advantage is that oral care composition of the invention has Improved gums healthy beneficial effect.Yet another advantage of the present invention is that providing, there are improved one or more antibacterial agents to enter The oral care composition of penetration depth in biomembrane.Yet another advantage of the present invention is that providing has improved one kind or more Kind antibacterial agent enters the oral care composition of the infiltration rate in biomembrane.Yet another advantage of the present invention is that providing for promoting High performance-price ratio and effective oral care composition into gums healthy.Another advantage is that oral care composition is to clean the teeth Agent, and pleasant taste and mouth feeling experience are preferably provided.Another advantage is oral care composition a series of There is physics and chemical stability under manufacture, processing and condition of storage.Even if another advantage is oral care composition 40 Also with stable end product quality (for example, consistent visual appearance and nothing fade, gums wound after being stored three months at DEG C Healing properties etc.).Another advantage is that oral care composition of the invention minimizes the use of antibacterial agent.Another advantage It is that oral cavity composition of the invention minimizes the amount of antifibrinolysis agent to reduce and/or eliminate shakiness as described above The qualitative and/or problem that fades.

In one aspect, the present invention relates to a kind of oral care compositions, which includes: a) by combination The poidometer 0.01% to 5% of object, preferably 0.05% to 4% stannous ion source；And b) based on the weight of composition 0.01% to 10%, preferably less than 5%, even more preferably less than 3%, still more preferably less than 1% antifibrinolysis Agent.

On the other hand, the present invention relates to a kind of oral care compositions, which includes: a) by combination The poidometer 0.01% to 5% of object, preferably 0.05% to 4% stannous ion source；And b) based on the weight of composition 0.01% to 10%, preferably less than 5%, even more preferably less than 3%, still more preferably less than 1% one or more chemical combination Object, one or more compounds are selected from tranexamic acid, ε aminocaproic acid, p-aminomethylbenzoic acid and their combination.

In another aspect of this invention, above-mentioned oral care composition also includes c) thickener, based on the weight of composition Preferably 0.01% to 5%, preferably 1% to 2.5% thickener, the thickener includes at least one examination selected from the following Agent, preferably at least two kinds of reagents: (i) linear sulphated polysaccharide；(ii) natural gum；(iii) nonionic cellulose derivatives； (iv) polyvinylpyrrolidone (PVP)；(v) polymer of more carboxylated vinyl main chains is included at least；(vi) polyacrylamide； (vii) containing the copolymer of acrylamide；(viii) pectin；(ix) protein；(x) polyethylene glycol (PEG), preferably high molecular weight PEG；And (xi) their combination.

In another aspect of this invention, above-mentioned oral care composition also includes d) based on the weight of composition 0% to small In 0.001% folic acid, or preferably free or substantially free of folic acid.

In another aspect of this invention, a kind of method of gums healthy for promoting people experimenter, this method are provided Including the oral care composition of the invention of the oral administration to subject, preferably once a day, more preferably twice daily.

When combine the appended claims read following specific embodiments when, these and other features of the invention for It will become obvious for those skilled in the art.

Detailed description of the invention

Although specification is finally particularly pointed out by claims and be distinctly claimed the present invention, it is believed that passing through The following drawings explanation, is better understood with the present invention.

Fig. 1 is for assessing the bleeding part for being used for the Mazza for the measurement for measuring improved gums wound healing and pointing out Timeline.

Fig. 2 is bar chart, provide for present composition embodiment 2 (comprising stannous and antifibrinolysis) with And the bleeding part quantity that positive and Mazza of the negative control at different time intervals (baseline, the 3rd day and the 4th week) is pointed out.

Fig. 3 is the perspective view for being attached with the oral cavity clamping plate of hydroxyapatite (" HA ") disk.

Fig. 4 is the perspective view for wherein having reeded HA disk.

Fig. 5 is the schematic cross sectional views of the wherein groove with biomembrane.

Fig. 6 is handled with present composition embodiment 2 (containing stannous and TA) or reference composition embodiment 9 (only Sn) The image of the wound healing of 24 hours people's gingival fibroblasts afterwards.

Specific embodiment

Definition

As used herein, it when in claim, is understood to refer to including the article of "one" and "an" It is one or more to be claimed or described substance.

Term " mitigation " and " alleviation " are used interchangeably, and refer to minimum, prevention, delay and/or processing gum disease At least one symptom of disease is to realize the positive change (that is, beneficial effect) to consumer.

As used herein, term " biomembrane " refers to the table in the closed bacterial flora of the matrix being adhering to each other and/or oral cavity Face or interface.

As used herein, term " includes " refers to the step of being added except specifically mentioned in addition to those and ingredient.The art Language includes term " Consists of " and "consisting essentially of ...".Composition of the invention may include, by and substantially by herein The basis of the present invention and restrictive condition and any additional or optional compositions as described herein, component, step Or restrictive condition composition.

As used herein, unless otherwise specified, term " dentifrice " refer to paste for cleaning oral surfaces, gel, Powder, tablet or liquid preparation.

As used herein, term " being free of " refers to the amount that the material is not present in composition.

As used herein, the beneficial effect that term " gingiva care " refers to the intrinsic of oral care composition or promotes, it is main It is used to alleviate one or more symptoms associated with early stage (i.e. the gingivitis) of gum disease.Such symptom may include Such as bleeding gums；With rubescent, swelling or gum edema.

As used herein, term " gums healthy " refers to that oral care composition provides consolidating for " gingiva care " beneficial effect There is or promote beneficial effect comprising at least improvement gums wound healing, and the additional reduction for improving bacterial activity is provided To mitigate the adverse effect of bacterium, because it includes that gingivitis, periodontitis or both are related with gum disease.

As used herein, term " improving gums wound healing " refers to the bleeding gums reduced in oral cavity, such as by any Determined by measurement described in the generally accepted measurement of bleeding gums in vitro or in vivo or test or embodiment 11.

As used herein, term " reduction for improving bacterial activity " refers to the bacterial activity reduced in oral cavity, such as by appointing In measurement and embodiment 13 described in what generally accepted measurement of antibacterial in vitro or in vivo or test or preferred embodiment 12 Determined by the external wound healing measurement.

As used herein, term " oral care composition " (" oral care composition " or " oral care Compositions ") refer to following product: the product retains the sufficiently long time in the oral cavity in common use process To contact some or all of dental surface and/or oral cavity tissue with the purpose for orally active.In an embodiment In, composition provides beneficial effect when being used for oral cavity.Oral care composition of the invention can be various forms, including tooth Gel, foam, weight, chewing gum, lipstick, sponge, tooth under cream, dentifrice, gutta-percha, tooth powder, tablet, gargle, mouthwash, gum Line, polishing paste, vaseline gel, Denture adhesive or artificial tooth product.In one embodiment, oral cavity composition is paste Or the form of gel.In another embodiment, oral cavity composition is the form of dentifrice.Oral cavity composition can also be mixed Onto band or film, to be used to directly applying or adhering to oral surfaces, or it is incorporated into dental floss.

As used herein, word " preferred ", " preferably " and their variant refer to is capable of providing in certain circumstances Embodiment of the present invention of specific beneficial effect.However, other embodiments can also be excellent under identical or other environment Choosing.In addition, the statement of one or more preferred embodiments is not offered as other embodiments and is disabled, and not It is intended to exclude other embodiments from the scope of the present invention.

As used herein, term " promotion " refers to promotion and/or enhancing and uses oral care of the invention in the oral cavity The associated gums healthy beneficial effect of composition.

As used herein, term substantially free refers to is added in composition or material without the material deliberately measured Amount account for composition less than 0.05%, 0.01% or 0.001%.

As used herein, term " collaboration gums healthy beneficial effect " refers to point of any two gums healthy beneficial effect Analyse measurable increase comprising the reduction of bacterial activity at least in improvement gums wound healing and improvement oral cavity, this is not only It is additive.

As used herein, term " tooth " refers to nature tooth and artificial teeth or artificial tooth.

As used herein, term " total water content " refers to free water and does not combine other ingredients in oral care composition Water.

Unless otherwise stated, otherwise all percentages, number and ratio are based on the total weight of the present composition.Unless Otherwise indicated, otherwise all such weight for being related to ingredients listed are based on active level meter, and therefore not including can The solvent or by-product being contained in commercially available material.

Unless otherwise specified, present document relates to all measurements carried out under 25 DEG C (i.e. room temperature).

Oral care composition

It was surprisingly found that antifibrinolysis agent in oral care composition, preferably tranexamic acid and stannous The combination of ion (i.e. antibacterial agent) is particularly useful for promoting the gums healthy beneficial effect of consumer.Specifically, astonishing Be the discovery that, when combining with tranexamic acid, stannous ion is penetrated into biomembrane and is significantly improved.It is not bound by the beam of opinion It ties up, tranexamic acid contains carboxyl and amine groups.It is believed that stannous ion can be tied strongly with the chemical part of these on tranexamic acid It closes, is penetrated into biomembrane with energetically influencing stannous ion.

It was also surprisingly found that when being prepared with tranexamic acid, stannous ion enter penetration depth in biomembrane and/ Or infiltration rate can increase or dramatically increase.In brief, there are tranexamic acids and stannous ion in oral care composition The combination in source facilitates composition and mediates the effect of bacterium is to the illeffects of gum in biomembrane.

In one aspect, the present invention relates to a kind of oral care compositions, which includes: a) by combination The poidometer 0.01% to 5% of object, preferably 0.05% to 4% stannous ion source；B) based on the weight of composition 0.01% To 10%, preferably less than 1% antifibrinolysis agent.Preferably, oral care composition also includes by composition Poidometer 0.01% to 5%, preferably 1% to 2.5% thickener, the thickener include at least one examination selected from the following Agent, preferably at least two kinds of reagents: (i) linear sulphated polysaccharide；(ii) natural gum；(iii) non-ionic cellulose or its spread out Biology；(iv) polyvinylpyrrolidone (" PVP ")；(v) polymer of more carboxylated vinyl main chains is included at least；(vi) polyacrylamide Amine；(vii) containing the copolymer of acrylamide；(viii) pectin；(ix) protein；(x) polyethylene glycol (" PEG ") is preferably high Molecular weight PEG；And (xi) their combination.

Antibacterial agent

The present invention relates to above-mentioned oral care compositions, and in preferred embodiments, which includes Stannous ion source, the stannous ion source is by 0.01% to 5% based on the weight of composition, and preferably 0.05% to 4%, or it is more excellent The amount of selection of land 0.1% to 2% exists to provide antibacterial effect.Stannous ion source used herein may include any safe and effective Tin salt.The suitable example of stannous ion source is selected from stannous chloride, stannous fluoride, stannous acetate, gluconic acid stannous, grass Sour stannous, stannous sulfate, lactic acid stannous, stannous tartrate, stannous iodide, chlorofluorination stannous, fluorozirconate, citric acid are sub- Tin, stannous maleate, glycine stannous, carbonic acid stannous, phosphoric acid stannous chloride, stannous pyrophosphate, metaphosphoric acid stannous and their group It closes.Preferably, stannous ion source is selected from stannous fluoride, stannous chloride and their combination.More preferably stannous ion source packet Include stannous chloride.The other examples of tin salt are found in United States Patent (USP) 5,578,293；Prencipe, M. and 5,281,410； Lukacovic,M.F.Other than stannous ion source, it also may include other ingredients for stablizing stannous ion, such as describe In United States Patent (USP) 5,004,597；Majeti, S. and 5,578,293；Ingredient in Prencipe, M.

Oral care composition of the invention is also optionally including other antibacterial agents, and the antibacterial agent is by the weight of composition Meter 0.035% or more, 0.05% to 2%, 0.1% to 1% amount exist.The example of these other antibacterial agents may include non- Cationic antibacterial agent, such as halogenated diphenyl ethers, phenolic compound (including phenol and its homologue), an alkyl and more alkane Base halogenated phenols and aromatic halophenols, resorcinol and its derivative, xylitol, bisphenol compound and halogenated N- salicyloyl benzene Amine, benzoic ether and halogenated N- phosphinylidyne diphenylamines.In addition useful antibacterial agent is enzyme, including endoglycosidase, papain, Dextranase, mutant enzyme and their combination.Such reagent is disclosed in United States Patent (USP) 2,946,725；Norris, P.E. and 4,051,234；In Gieske, H.A.The example of other antibacterial agents includes Chlorhexidine and flavored oils such as thymol.At another In example, other antibacterial agents may include triclosan (the chloro- 2- of 5- (2,4- dichlorophenoxy) phenol).

Antifibrinolysis agent

The invention further relates to above-mentioned oral care compositions, in preferred embodiments, the oral care composition packet Agent containing antifibrinolysis.Preferably, antifibrinolysis agent is the compound of formula (I):

H₂N-X-COOH (I)

Wherein X is branch or non-branched, saturated or unsaturated aliphatic group；Or aromatic group.

As used herein, term " aliphatic group " include saturation and unsaturated, non-branched (i.e. straight chain) and branch, it is acyclic, The cyclic annular or polycyclic aliphatic hydrocarbons containing 1 to 20 carbon atom, they optionally replace.Aliphatic group is intended to include herein But it is not limited to the group of such as alkyl, alkenyl, alkynyl, alkylidene, alkenylene, alkynylene and cycloalkyl moiety.

As used herein, term " aromatic group " refers to aryl rings, and include but is not limited to only be made of hydrogen and carbon and Monocycle or polycyclic hydrocarbon ring system containing 6 to 18 carbon atoms, wherein ring system can be fractional saturation.Unless in the present specification It is otherwise noted, otherwise aromatic ring optionally replaces.Aromatic group be intended to include but be not limited to herein such as phenyl, naphthalene and The group of fluorenyl.

Term " cyano " refers to-CN functional group.

Term " halogenated " or halogen itself or a part as another substituent group refer to fluorine, chlorine, bromine or iodine atom.

Term " oxo " refers to=O substituent group.

" alkyl " refers to the group containing the linear chain or branched chain hydrocarbon chain being only made of carbon and hydrogen atom, without containing unsaturation Group has 1 to 20 carbon atom, preferably 1 to 12 carbon atom, preferably 1 to 8 carbon atom, or preferably 1 to 6 Carbon atom, and it is connected by the rest part of singly-bound and molecule, for example, methyl, ethyl, propyl, 1- Methylethyl (isopropyl Base), butyl, amyl etc..Alkyl, which can be, optionally to be replaced.

" alkenyl " refers to containing the group for the linear chain or branched chain hydrocarbon chain being only made of carbon and hydrogen atom, contains at least one Carbon-to-carbon double bond has 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, or preferably 1 to 8 carbon atom, for example, second Alkenyl, propyl- 2- alkenyl, but-1-ene base, amyl- 1- alkenyl, amyl- 1,4- dialkylene etc..Alkenyl, which can be, optionally to be replaced.

" alkynyl " refers to containing the group for the linear chain or branched chain hydrocarbon chain being only made of carbon and hydrogen atom, contains at least one Carbon-carbon triple bond has 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, or preferably 1 to 8 carbon atom, for example, second Alkynyl, propinyl, butynyl, pentynyl, hexin base etc..Alkynyl, which can be, optionally to be replaced.

" alkylidene " or " alkylidene chain " refers to containing the remainder of molecule to be connected to the base being only made of carbon and hydrogen The group of the linear chain or branched chain hydrocarbon chain of group does not contain unsaturated group, and has 1 to 12 carbon atom, for example, methylene Base, ethylidene, propylidene, butylidene etc..Alkylidene, which can be, optionally to be replaced.

" alkenylene " or alkenylene chain ", which refers to, is connected to the straight of the group being only made of carbon and hydrogen for the remainder of molecule Chain or branch hydrocarbon chain contain at least one carbon-to-carbon double bond, and have 2 to 20 carbon atoms, preferably 2 to 12 carbon originals Son, for example, ethenylidene, allylidene, butenylidene etc..Alkenylene, which can be, optionally to be replaced.

" alkynylene " or " alkynylene chain ", which refers to, is connected to the group being only made of carbon and hydrogen for the remainder of molecule Linear chain or branched chain hydrocarbon chain contains at least one carbon-carbon triple bond, and has 2 to 20 carbon atoms, for example, sub- propinyl, Asia Butynyl etc..Alkynylene, which can be, optionally to be replaced.

" naphthenic base " refers to the stable saturation monocycle or polynucleation hydrocarbon group being only made of carbon and hydrogen atom, may include thick Ring system or bridged-ring system have 3 to 15 carbon atoms, it is therefore preferred to have 3 to 10 carbon atoms or preferably 3 to 7 carbon Atom, for example, hexamethylene.Naphthenic base, which can be, optionally to be replaced.

" halogenated alkyl " refers to the alkyl as defined above replaced by one or more halogen groups, for example, trifluoromethyl, The bromo- 2- fluoropropyl of difluoromethyl, trichloromethyl, 2,2,2- trifluoroethyl, 1,2- bis-fluoro ethyls, 3-, 1,2- dibromoethyl etc..Halogen Substituted alkyl, which can be, optionally to be replaced.

" heterocycle " refer to stable 3 yuan that are made of 2 to 20 carbon atoms and 1 to 6 hetero atom to 24 yuan of saturated rings, The hetero atom is selected from the atom being made of nitrogen, oxygen or sulphur.Unless being otherwise noted in the present specification, otherwise heterocycle can be list Ring, bicyclic, tricyclic or Fourth Ring ring system may include fused ring system or bridged-ring system；And nitrogen, carbon or sulphur atom in heterocycle It can be and optionally aoxidize；Nitrogen-atoms can be optionally quaternized.Heterocycle, which can be, optionally to be replaced.

" Heterocyclylalkyl " refers to formula-R_aR_eFunctional group, wherein R_aFor alkylidene as defined above, and R_eIt is as above fixed The heterocycle of justice, and if heterocycle is nitrogen heterocycle, heterocycle can be connected to alkylidene at nitrogen-atoms.Heterocycle alkane Base, which can be, optionally to be replaced.

" heteroaryl " refers to 5 yuan to 20 yuan aromatic rings being made of 1 to 17 carbon atom and 1 to 3 hetero atom, the miscellaneous original Son is selected from the atom being made of nitrogen, oxygen and sulphur.Heteroaryl can be monocycle, bicyclic, tricyclic or Fourth Ring ring system, may include condensed ring System or bridged-ring system.Heteroaryl, which can be, optionally to be replaced.

" heteroaryl alkyl " refers to formula-R_aR_fFunctional group, wherein R_aFor alkylidene as defined above, and R_fIt is as above The heteroaryl of definition.Heteroaryl alkyl, which can be, optionally to be replaced.

The event for the case where " optionally replacing " refers to subsequent description may or may not occur, and the description includes the thing Part or the situation happened and the situation not occurred.For example, unless otherwise specified, " optionally replacing " refers to that chemical part can Or it can not be replaced by the one or more in following group: alkyl, alkenyl, halogen, halogenated alkenyl, cyano, nitro, aryl, ring Alkyl, heterocycle, heteroaryl, oxo ,-OR¹、-OC(O)-R¹、-NR(¹)₂、-C(O)R¹、-C(O)OR¹、-C(O)N(R¹)₂、-N (R¹)C(O)OR²、-N(R¹)C(O)R²、-N(R¹)S(O)_tR²(wherein t is 1 to 2) ,-S (O)_tOR²(wherein t is 1 to 2) ,-S (O)_xR²(wherein x is 0 to 2) and-S (O)_tN(R¹)₂(wherein t is 1 to 2), wherein each R¹It independently is hydrogen, alkyl, halogenated It is alkyl, naphthenic base, cycloalkyl-alkyl, aryl (optionally being replaced by one or more halogen groups), aralkyl, heterocycle, miscellaneous Naphthenic base, heteroaryl or heteroaryl alkyl；And each R²For alkyl, halogenated alkyl, naphthenic base, cycloalkyl-alkyl, aryl, virtue Alkyl, heterocycle, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl, and unless otherwise specified, each of above-mentioned substituent group It is unsubstituted.

Preferably, antifibrinolysis agent be selected from tranexamic acid, ε aminocaproic acid, p-aminomethylbenzoic acid or they Combination.Preferably, antifibrinolysis agent by based on the weight of composition 0.1% to less than 1%, preferably 0.2% to 0.7%, or more preferably 0.25% to 0.55% amount exists.Preferably, antifibrinolysis agent is tranexamic acid (" TA "), with chemical name trans-4-amino methyl-cyclohexyl alkane carboxylic acid (CAS 1197-18-8) and following structural formula (II):

Tranexamic acid is the antifibrinolysis agent of a kind of cracking for preventing fibrin clot or dissolution.It has Help stable fibers fibrin clot, it maintains blood coagulation and helps to control bleeding.Tranexamic acid be described as non-antibacterial and And for inhibiting gums inflammation, bleeding and/or swelling highly effective (referring to United States Patent (USP) 4,272,513；Gaffar,A.).Art Language " tranexamic acid " includes acid in itself or with the active bioprecursor of required antihaemorrhagics or its salt.Preferably, tranexamic acid It can be used in free acid form or in the form of the acceptable salt in its oral cavity, preferably water-soluble, such as alkali metal containing (example Such as, Na or K), ammonium or C₁-C₈Monosubstituted ammonium, two replace ammoniums or three replace ammoniums (for example, alkanol replace, such as monoethanol ammonium, two Ethyl alcohol ammonium or triethanol ammonium) cation.Tranexamic acid can be withIt is commercially available.Alternatively, can it is cis- from its- Trans mixture synthesis or separation tranexamic acid are (referring to United States Patent (USP) 3,499,925；Naito,T.).

It has been found that can solve above-mentioned tranexamic acid stability by reducing the tranexamic acid concentration in composition and fade Problem.It was surprisingly found that only the smallest of reduction amount, the tranexamic acid such as based on the weight of composition less than 1%, it can Its stability and formula compatibility is set to generate materials variances.Due in preferred oral care compositions of the invention by ammonia first ring Effect, the potential synergistic effect that acid is combined with stannous ion, reduced tranexamic acid level will not be to its gums wound healing Activity and/or effect have a negative impact.It is without being bound by theory, it is believed that stannous ion can be changed with these on tranexamic acid The department of the Chinese Academy of Sciences point is strong to be combined, energetically to influence to permeate, to keep enough effects under low concentration.

In another embodiment, antifibrinolysis agent is ε aminocaproic acid (" EACA ").Preferably, EACA with 0.01% to 5% based on the weight of composition, preferably 0.1% to 1%, or even more preferably less than 1% amount exists.EACA tool There are chemical name 6- amino-caproic acid (CAS 60-32-2) and following structure formula (III):

ε Aminocaproic Acid and the like can be with trade nameIt is commercially available.Term " ε aminocaproic acid " includes acid Itself has the active bioprecursor of required antihaemorrhagics or its salt.It is the derivative of amino acid lysine, and is one Kind antiplasmin agent.It is similar with tranexamic acid, the problem that fades can be also introduced in oral care composition using ε aminocaproic acid (referring to United States Patent (USP) 4,649,044；Gomi,T.).The previous oral care composition of unstability and the problem that fades has been described It is prepared with ε aminocaproic acid, level is for 0.05% to 1% (referring to United States Patent (USP) 4,272,513；Gaffar, A. and 4,272, 512；Embodiment in Gaffar, A.).It is without being bound by theory, it is believed that fade and be attributable to ε aminocaproic acid and flavor ingredients In aldehyde group reaction.To avoid fading, above-mentioned bibliography proposes to introduce cyclodextrin and use substantially free of aldehyde group Flavor ingredients.However, the solution is undesirable, because it complicates formula and limits workable seasoning The type of agent material.On the contrary, present invention promotion combines ε aminocaproic acid to overcome the above problem with stannous ion.

In another embodiment, antifibrinolysis agent is p-aminomethylbenzoic acid (" PAMBA ").It is preferred that Ground, PAMBA is by 0.01% to 5% based on the weight of composition, and preferably 0.1% to 1%, or even more preferably less than 1% amount In the presence of.P-aminomethylbenzoic acid (CAS 56-91-7) has following structure formula (IV):

Term " p-aminomethylbenzoic acid " include acid itself or have the active bioprecursor of required antihaemorrhagics or its Salt.

Thickener

Preferably, oral care composition of the invention may include one or more thickeners, more preferably at least two kinds Thickener.Preferably, thickener is by 0.01% to 10% based on the weight of composition, preferably 1% to 2.5% amount exists. Specifically, the invention further relates to above-mentioned oral care compositions, and in preferred embodiments, which includes Thickener selected from the following:

(i) linear sulphated polysaccharide is carrageenan；

(ii) natural gum is selected from xanthan gum, karaya gum, gum arabic, bassora gum and their combination；

(iii) non-ionic cellulose or derivatives thereof, the non-ionic cellulose or derivatives thereof have in 50,000 dongles To within the scope of 1,300,000 dalton average molecular weight and preferably 300 to 4,800 average degree of polymerization；

(iv) more carboxylated vinyl main chains and polymer selected from the following: maleic anhydride and methyl vinyl ether are included at least Copolymer, the copolymer have 30,000 dalton to 1,000,000 dalton molecular weight；The homopolymer of acrylic acid；With And the copolymer of maleic acid and acrylic or methacrylic acid；And

(v) their combination.

Preferably, oral care composition according to the present invention, wherein thickener is selected from: (i) carrageenan is selected from κ-angle Pitch dish glue, ι-carrageenan, λ-carrageenan and their combination；(ii) natural gum is xanthan gum；(iii) nonionic Cellulose or derivatives thereof is hydroxyethyl cellulose (" HEC ")；(iv) copolymer of maleic anhydride and methyl vinyl ether be with It is at least one of lower: Gantrez AN139 (M.W.500,000 dalton), Gantrez AN119 (M.W.250,000 dongle ) or S-97 pharmaceutical grade (M.W.70,000 dalton)；With the homopolymer and maleic acid and acrylic acid or methyl-prop of acrylic acid The copolymer of olefin(e) acid be at least one of the following: Acusol 445, Acusol 445N, 531 Accusol, Acusol 463, Acusol 448、Acusol 460、Acusol 465、Acusol 490、Sokalan CP5、Sokalan CP7、Sokalan CP45 or Sokalan CP12S；And (v) their combination.

In this example, GANTREZ^TMSeries polymer is the copolymer of maleic anhydride and methyl vinyl ether, has 30, The molecular weight (M.W.) of 000 dalton to 1,000,000 dalton.These copolymers can be with such as GANTREZ^TMAN139 (M.W.500,000 dalton), AN119 (M.W.250,000 dalton) and S-97 pharmaceutical grade (M.W.70,000 dalton) from Ashland Chemicals (Kentucky, USA) is bought.

In another example, ACUSOL^TMWith SOKALAN series polymer include acrylic acid homopolymer and maleic acid and The copolymer of acrylic or methacrylic acid.Example is the 0:1000 with about 2,000 to about 1,000,000 molecular weight (M.W.) To the maleic acid of 1000:0 and the copolymer of acrylic acid.These copolymers can be with ACUSOL^TM445 and 445N, ACUSOL^TM531、 ACUSOL^TM463、ACUSOL^TM448、ACUSOL^TM460、ACUSOL^TM465、ACUSOL^TM497、ACUSOL^TM490 from Dow Chemicals (Michigan, USA) is commercially available, and withCP 5、CP 7、 45 He of CP12 S of CP is commercially available from BASF (New Jersey, USA).

Anti-caries agent

Oral care composition may include a effective amount of anti-caries agent.In one aspect, anti-caries agent is fluoride ion Source.The amount that fluoride sources can be enough to provide certain fluorinion concentration in the composition at 25 DEG C exists, and/or can be by group Close object poidometer 0.0025% to 2%, or preferably 0.5% to 1.5% level using to provide anti-caries tooth effect.It is various The material that various kinds generates fluorine ion is used as soluble fluoride source in the present invention.It is special that the example of fluorine ion is disclosed in the U.S. Benefit 3,535,421；Briner, W.W. and 3,678,154；In Widder, J.S..The suitable example of fluorine ion can be selected from Sodium fluoride, indium, amine fluoride, sodium monofluorophosphate (" MFP "), potassium fluoride, zinc fluoride and their mixture source.

Antiplaque agent

Oral care composition may include one of antiplaque agent or anticalculus agent or a variety of, to press the weight of composition The amount of meter 0.001% to 20% or 0.1% to 5% exists.Non-limiting example may include pyrophosphate as pyrophosphate Ion source.Other examples are disclosed in United States Patent (USP) 8,691,190；Haught, J.C., in the 55th section.

pH

The pH of oral care composition can be 4.5 to 11, or preferably 5 to 10.Made according in oral care composition Active material, it may be necessary to different pH.For the preparation containing stannous fluoride, it may be desirable to have than typically cleaning the teeth The slightly lower pH of agent.Usually using the paste of 1:3: the ratio of water measures pH, thus by 1 gram of oral care composition (for example, tooth Cream) it is mixed into 3 grams of deionized waters, and then assessed using the pH probe received in the industry calibrated at ambient conditions pH.PH is measured by the pH meter with auto thermal compensation (ATC) probe.PH meter can be read to 0.001pH unit.

After each use, using water washing electrode, to be free of sample solution.By with thin paper such as Kimwipes or equally Object wipes to remove any extra water.When electrode is not in use, holding electrode tip immerses 7 buffer solution of pH or electrode In storage solutions.Device specifics are as follows:

PH meter: it can read to the measuring instrument of 0.01 or 0.001pH unit.

Electrode: Orion Ross Sure-Flow combination: Glass body-VWR#34104-834/Orion#8172BN or VWR#10010-772/Orion#8172BNWP。

Body of epoxy resin-VWR#34104-830/Orion#8165BN or VWR#10010-770/Orion# 8165BNWP。

Semimicro body of epoxy resin-VWR#34104-837/Orion#8175BN or VWR#10010-774/Orion# 3175BNWP。

Orion PerpHect combination: VWR#34104-843/Orion#8203BN semimicro Glass body.

ATC probe: Fisher Scientific, Cat.#13-620-16.

PH buffer

The oral care composition of this paper may include that a effective amount of buffer or pH regulator refer to as used herein It can be used for for the pH of oral care composition being adjusted to the reagent of pH range identified above.Buffer includes alkali metal hydroxide Object, ammonium hydroxide, organoammonium compound, carbonate, sesquicarbonate, borate, silicate, phosphate, imidazoles and they Mixture.

Specific buffer include monosodium phosphate (sodium dihydrogen phosphate), tertiary sodium phosphate (Trisodium phosphate dodecahydrate or TSP), sodium benzoate, benzoic acid, sodium hydroxide, potassium hydroxide, alkali carbonate, sodium carbonate, imidazoles, pyrophosphate, grape Sodium saccharate, lactic acid, sodium lactate, citric acid, sodium citrate, phosphoric acid.

In one embodiment, using 0.01% to 3% based on the weight of composition, preferably 0.1% to 1% TSP, and 0.001% to 2% based on the weight of composition, preferably 0.01% to 0.3% monosodium phosphate.It is not bound by opinion Constraint, TSP and monosodium phosphate can have calcium ion sequestering activity, and therefore provide some mono-fluor phosphate stability and (containing Have in those of mono-fluor phosphate preparation).

Water

Water is usually used as the carrier material in oral care composition because of its multiple beneficial effect.For example, water can be used as Processing aid, it is mild to oral cavity and facilitate toothpaste fast foaming.Water can be used as a kind of ingredient in such a way that its own is suitable It is added, or can be used as carrier and be present in other common raw material such as sorbierite and NaLS.

The oral care composition of this paper may include 10% to 70% based on the weight of composition, or preferably 15% to 30% total water content.As used herein, term " total water content " refers to the total amount of water present in oral care composition, nothing Solvent or carrier addition by being added separately into or as other raw material, but exclude to tie present in certain inorganic salts Brilliant water.Preferably, water is USP water.

Seasoning composition

The oral care composition of this paper may include 0.01% to 5% based on the weight of oral care composition, preferably 0.1% to 2% seasoning composition.The example that can be used for the suitable flavoring agent of seasoning composition includes United States Patent (USP) 8, 691,190；Haught, J.C., those of described in the 39th section and the 40th to 45 section.Preferably, seasoning composition includes:

(i) flavouring mixture, the flavouring mixture include based on the weight of seasoning composition be greater than 0% to less than 55% or the gaultherolin greater than 65% to 95%；Based on the weight of seasoning composition be greater than 0% to less than 30% or Menthol greater than 35% to 65%；It is greater than 0% to less than 1% based on the weight of seasoning composition or greater than 5% to 50% Eugenol；And it is greater than 0% to less than 3% or the cineole greater than 8% to 30% based on the weight of seasoning composition； Or

(ii) free or substantially free of gaultherolin, menthol, eugenol and the flavouring mixture of cineole.

Sweetener

The oral care composition of this paper may include sweetener.Sweetener is in oral care composition usually by combination The horizontal of the poidometer 0.005% to 5% of object exists.The suitable examples of sweetener include saccharin, glucose, sucrose, lactose, wood Sugar alcohol, maltose, fructose, aspartame, sodium cyclamate, D-trp, dihydrochalcone, acesulfame, Sucralose, knob Sweet tea and their mixture.Other suitable examples of sweetener are described in United States Patent (USP) 8,691,190；Haught,J.C. In.

Colorant

The oral care composition of this paper may include colorant, the colorant by based on the weight of composition 0.001% to 0.01% amount exists.Colorant can be the form of aqueous solution, the preferably aqueous solution of 1% colorant.Colorant it is suitable Example may include pigment, remover, filler powder, talcum, mica, magnesium carbonate, calcium carbonate, bismuth oxychloride, zinc oxide and The material of other visions that can change oral care composition.Other suitable examples may include titanium dioxide (TiO₂).Two Titanium oxide is white powder, increases opacity for composition, and usually 0.25% to 5% based on the weight of composition Level be present in oral care composition.

Surfactant

The oral care composition of this paper may include surfactant, and the surfactant is based on the weight of composition 0.1% to 50%, 0.025% to 9%, 0.05% to 5%, 0.1% to 2.5%, 0.5% to 2% or 0.1% to 1% amount In the presence of.Surfactant can be selected from anionic surfactant, nonionic surfactant, amphoteric surfactant, both sexes from Sub- surfactant, cationic surfactant or their mixture.The suitable example of anionic surfactant can wrap It includes and is described in United States Patent (USP) 8,691,190；Haught, J.C., those of in the 32nd section, the 33rd section, the 34th section and the 35th section.Two The suitable example of property ionic surface active agent or amphoteric surfactant is described in United States Patent (USP) 8,691,190；Haught, J.C., in the 36th section, the suitable example of cationic surfactant is described in the 37th section, and nonionic surfactant Suitable example be described in the 38th section.

Wetting agent

The oral care composition of this paper may include wetting agent, the wetting agent by 0% to 70% based on the weight of composition, Or 15% to 55% amount exists.Wetting agent prevents oral care composition to be hardened because being exposed to air, and certain wet Agent can also assign Dentrifice composition desired sweet taste flavor.The suitable example of wetting agent may include glycerol, sorbierite, poly- second Glycol, propylene glycol, xylitol, trimethylglycine and their mixture.Other examples may include other edible more First alcohol.

Grinding agent

The oral care composition of this paper also may include one or more grinding agents, and one or more grinding agents are to press group The amount for closing the poidometer 0.1% to 60% or 1% to 50% or 2% to 40% or 4% to 30% of object exists.Suitably show Example may include precipitated silica, fused silica, calcium carbonate, Tri-Compress, phosphate (including orthophosphates), Pyrophosphate, perlite, float stone, Nano diamond, surface treated and the precipitated silica of dehydration, rice hull silica, Silica gel, aluminium oxide, polymetaphosphate, other inorganic particles and their mixture.It can be used for the abrasive materials of this paper Other examples include Bibasic Calcium Phosphate dihydrate, calcium pyrophosphate, tricalcium phosphate, calcium polymetaphosphate, insoluble poly-metaphosphoric acid Sodium, hydrated alumina, β calcium pyrophosphate, calcium carbonate and resinous abrasive materials such as urea and formaldehyde particulate condensation products, with And such as it is disclosed in United States Patent (USP) 3,070,510；Other materials in Cooley, W.E..

Anti-allergic agent

The oral care composition of this paper may include anti-allergic agent, and the anti-allergic agent is based on the weight of composition 0.001% to 20% or 0.1% to 5% amount exists.The suitable example of anti-allergic agent may include being described in United States Patent (USP) 8, 926,949；The 41st section of Dayanim, R. and U.S. Patent Publication 2009/0311200；Those of in the 59th section of Lambert, P..

Whitening agent and oxidant

The oral care composition of this paper may include whitening agent or oxidant, and the whitening agent or oxidant are by composition The amount of poidometer 0.01% to 30% or 0.1% to 10% or 0.5% to 5% exists.Suitable example may include peroxidating Hydrogen, urea peroxide, calper calcium peroxide, sodium peroxide, zinc peroxide or their combination.Other examples are to be described in United States Patent (USP) 8,691,190；Haught, J.C., those of in the 56th section.

Anti-inflammatory agent

The oral care composition of this paper may include a effective amount of anti-inflammatory agent.Suitable example may include that be described in the U.S. special Benefit announces 2011/0104081, Scott, D.C., those of in the 55th section.

Anti-calculus agent

The oral care composition of this paper may include anti-calculus agent, and the anti-calculus agent is based on the weight of composition 0.05% to 50% or 0.05% to 25% or 0.1% to 15% amount exists.Suitable example may include being described in the U.S. Patent disclosure 2011/0104081, Scott, D.C., the 64th section and U.S. Patent Publication 2012/0014883；Scott, D.G., Those of in 63rd to 68 section.

Chelating agent

The oral care composition of this paper may include a effective amount of chelating agent, also referred to as sequestering agent, be permitted in them Mostly also there is anti-calculus dentalis activity or tooth affinity agent activity.The use of chelating agent is for their complexing calciums in oral care product (being such as found in the cell wall of bacterium) is destroyed dental plaque and is advantageous with the ability of complexing of metal ion.Ion is such as The chelating of iron or copper helps to postpone finished product oxidation deterioration.The suitable example of chelating agent may include being described in U.S. Patent Publication 2011/0020246；Those of in 21 to 28 sections of Strand, R., the.

Tooth affinity agent

The oral care composition of this paper may include a effective amount of tooth affinity agent.For the purpose of present patent application, tooth Tooth affinity agent is also included as chelating agent.Suitable example may include polymeric surfactant (" PMSA "), including poly- electricity Xie Zhi, more specifically anionic polymer.Other examples may include being described in U.S. Patent Publication 2012/0014883；Scott, D.G., those of in the 74th to 84 section.

Analgesic and anesthetic

The oral care composition of this paper may include a effective amount of analgesic or anesthetic.Suitable example may include description In United States Patent (USP) 9,005,585；Deckner, G.E., those of in the 117th section.

Other ingredients

Oral care composition of the invention may include well known by persons skilled in the art common and conventional helper component. It should be appreciated that selected oral care composition component must be chemically and physically compatible with each other.

Application method

In one aspect, the present invention relates to a kind of methods for cleaning or polishing the tooth of people experimenter.This paper's is clear Clean or polishing method includes contacting the tooth of subject with oral care composition according to the present invention.

On the other hand, the invention further relates in people experimenter promote gums healthy method, this method include to by The oral administration of examination person oral care composition according to the present invention.Preferably, the method for gums healthy is promoted at least to be selected from Occur in period below:

A) 0 hour to 72 hours；

B) 0 hour to 48 hours；

C) 0 hour to 24 hours；

Wherein 0 hour is when applying oral care composition according to the present invention.

On the other hand, the invention further relates to the method for promoting gums healthy, wherein gums healthy is selected from:

(i) improve the gums wound healing in oral cavity；

(ii) improve the reduction of bacterial activity in oral cavity；Or

(iii) their combination.

Method as described above can be by scrubbing (such as brushing teeth) with oral care composition (for example, dentifrice) or using mouth Chamber care composition (for example, dentifrice slurry or mouthwash) rinses.Oral care composition pure can be applied or via delivering Device such as toothbrush is applied.Other methods include by locally buccal cavity gel, mouth spraying agent, toothpaste, dentifrice, gutta-percha, Under tooth powder, tablet, gum gel, foam, weight, chewing gum, lipstick, sponge, dental floss, vaseline gel or artificial tooth product or its Its form is contacted with the tooth of subject and oral mucosa.According to the embodiment, oral care composition can as toothpaste that Sample frequently uses, or can less frequently use, such as once a week, or by professional with polish paste or it is other plus The form of strong inorganic agent uses.

Embodiment

The following example and description further illustrate the embodiment in the scope of the invention.These given embodiments Purpose only for the purpose of illustration, is not considered as limitation of the present invention because do not depart from essence of the invention and In the case where range, many changes can be carried out to it.

A: embodiment 1 to 10

Embodiment 1 to 10 is Dentrifice composition as follows, and wherein the amount of component is in terms of weight %.They can pass through It is suitably prepared by the conventional method that formulator selects.Embodiment 1 to 6 is invention formulation according to the present invention, is used respectively The stannous ion source (such as stannous chloride) and single antifibrinolysis agent (such as TA, EACA or PAMBA) of two kinds of concentration Preparation.Embodiment 7 is the invention formulation prepared with stannous chloride and two kinds of antifibrinolysis agent (such as TA and EACA). Meanwhile preparing control formulation embodiment 8 to 10.Embodiment 8 is prepared in the case where no stannous ion source, and embodiment 9 is not having It is prepared in the case where having antifibrinolysis agent, and embodiment 10 is prepared in the case where no any component.With shown Ratio prepares all compositions by the mixture of component in table 1 and 2.

Table 1: present composition embodiment 1 to 7

Table 2: reference composition embodiment 8 to 10

Embodiment 11- is used to measure the measurement for improving gums wound healing in oral cavity

Measurement is for determining for oral care composition of the invention and control oral care composition in oral cavity below In gums wound healing improvement.The measurement includes mildly detecting gums gap to assess whether that there are bleedings.Gingivitis root Bleeding index (" PBI ", and according to Muhlemann, H.R.:J.Prev.Dent.1977 is examined to the spy of gum nipple according to Mazza；4:6) Modification assessed, otherwise referred to as " Mazza index ", to determine the quantity (being defined by Mazza, 1981) of bleeding part. For this measurement, detected at most 56 positions on the centre and remote middle tongue surface of each tooth.Probe is set Depth in gingival sulcus to about 0.5mm to 1.0mm, and spot scan interdental papilla is inserted into from it along the soft tissue direction of ditch Tip.Before carrying out the measurements, all faces or lingual surface of each quadrant are scanned.It is surveyed since first dental scans Amount.

Using the oral soft tissue and gingivitis inspection of Mazza index in baseline (i.e. 0 hour), the 3rd day and the 4th Zhou Shijin Row.The definition of Mazza index is as shown in table 3.

Table 3: for measuring the Mazza index of gingiva bleeding gingival hemorrhage

Scoring	Explanation
		0	The gums (i.e. no color change) normally occurred, and while detecting, does not have bleeding.
1	Color change and inflammation-related, but while detecting, does not have bleeding.
		2	A slight bleeding at detecting.
3	It bleeding and is flowed in gingival edge since detecting.
		4	It bleeds profusely and overflows gingival edge.
5	Hematostaxis is without detecting.

Experiment carries out in Procter&Gamble (Beijing) oral care portion, Science and Technology Ltd., and obtains the Beijing P&G skill The approval of art center (China) institutional review board, and meet the declaration of Helsinki World Medical Association (revising within 1996).It abides by Follow the ICH guide of drug clinical trial quality management practices (" GCP ").

Firstly, the subject for meeting research attendance request is randomized to either processing group or control group, it is randomized using SAS Program balances baseline Mazza index score.Individual including meeting following standard: over 18 one full year of life；Possess minimum 12 naturally Labial teeth；With at least five bleeding part (i.e. baseline) for such as passing through Mazza index measurement when first medical；With gingivitis Rather than periodontitis；Based on medical history/update review to research is participated in, good one such as determined by researcher/designated person As health status.Personal exclusion criteria includes: serious periodontosis, it is characterized in that purulent exudate, general activity and/or Slump of disastrous proportions；The preoperative illness for dentistry prevention of any required antibiotic；It self is reported during research process and nursing women It accuses pregnancy or is intended to pregnancy；Atypia in gingival tissues fades or pigmentation；Fixed face orthodontic appliance；Gingival tissues In atypia fade or pigmentation；Use antibiotic at any time during research；It is any can expectability subject can be interfered to pacify The full disease or illness for completing research.The clinical parameter of each subject is monitored in entire research.Meet of exclusion criteria People, which is excluded, to be participated in except research.

Research is 4 weeks, double blind and parallel group.With from negative control group, positive controls and processing (i.e. present invention combination Object) group product treatment subject.Negative control group receives conventional fluorinated toothpaste product (for example, 0.321% sodium fluoride-Cavity Protection Product, lot number 60771864AA, 2018.03.17) (" CCP product ").It is positive right Receive commercially available Chinese medicine and TA preparation Yunnan Baiyao willow herb product, lot number 20190408F05 (" YNBY product ") according to group.Processing group Receive any one of present composition as disclosed in embodiment 1 to 7, contains stannous chloride and one or more anti-fibres Fibrillarin lytic agent.Each of control or processing branch are locally applied to tooth/gum surfaces twice daily, for 4 weeks Time.Mazza Index Assessment is carried out to subject, in baseline, the 3rd day and the 4th week (studying terminates) to bleeding portion The reduction of position is scored, as shown in Figure 1.Data are analyzed with the analysis of covariance (" ANCOVA "), wherein using statistical analysis system (" SAS ") is united using respective baseline as model covariant.

As a result: 150 Eligible subjects complete research.Processing group receives present composition embodiment 2.Control group It is balanced on age and gender with processing group.Baseline average balances (p > 0.43) between control group and processing group.To being based on The result of the bleeding part quantity of the control group and processing group of Mazza index carries out average (and their confidence interval), and And it is then plotted as bar chart, as shown in Fig. 2, so as to being compared between control group and processing group.Obtain the p of product difference It is worth, wherein p < 0.01.

Influence Fig. 2 shows Sn and TA to the gingiva bleeding gingival hemorrhage reduction of present composition embodiment 2.Referring to Fig. 2, this hair Bright composition embodiment 2 (containing both TA and Sn) averagely has 10.7 bleeding parts on day 3, and average at the 4th week With 6.73 bleeding parts, and positive control YNBY product averagely has 11.67 bleeding parts on day 3, and the 4th Zhou Pingjun has 8.49 bleeding parts.Negative control CCP product (it is without containing Sn and does not contain TA) the 3rd balance all has 15.01 bleeding parts, and the 4th week averagely has 13.41 bleeding parts.As a result it shows, implements in the present composition In example 2, Sn is added in TA and provides between baseline and the 4th week bleeding part quantity and reduces (that is, about -10 bleeding portions Position) bigger improvement, and only have in the quantity at same period internal haemorrhage position with the positive control YNBY product of TA Lesser reduction (that is, about -5 bleeding parts).In research in 4 weeks, negative control CCP product (its without containing Sn and Without containing TA) moderate reduction (that is, about -2 bleeding parts) are only shown in the quantity of bleeding part.

The result shows that antifibrinolysis agent and the combination of antibacterial agent (for example, stannous ion source) provide the tooth of enhancing Gum antihaemorrhagics effect.In fact, present composition embodiment 2 shows the antifibrinolysis agent of reduced levels (i.e. 0.50%TA) the effect of.This is favourable, because it is known that effective certain antifibrinolysis agent (such as TA, EACA etc.) Can cause oral care composition fade and instability problem, under the higher concentration especially for providing effect.Cause Both this, is by using reduced levels, will avoid fading with unstability.

B: for measuring the measurement for improving antibacterial agent infiltration in biomembrane

In order to determine permeability of the antibacterial agent in biomembrane, measured below for the present invention for the present invention and control Oral care composition the common location percentage of stannous ion and bacterium is assessed via plaque biofilm in situ.What is measured is thin Section is described as follows.

(a)Matrix for biofilm development

Hydroxyapatite (" HA ") disk is used for the growth in situ of biomembrane.HA disk is designed to tool in each disk, and there are three flat Capable groove (is 200 μm wide for grooves on two sides；200 μm of depths；And be 500 μm wide and 500 μm of depths for intermediate groove).It will When disk is attached to the mouth of subject, these grooves please be keep vertical, to imitate gap between interdental neighbour, this is that dental plaque is logical Often be easy to gather is difficult to clean region.Undisturbed dental plaque is collected in model permission from groove.HA disk by Shanghai Bei'erkang biomedicine limited company manufacture.

(b)Wear clamping plate

Human Trials wear clamping plate.Each subject at most wears 12 HA disks on clamping plate, after ensuring 48 hours At least nine HA disk is available.The non-limiting example of such clamping plate and HA disk is shown in Fig. 3.Referring to Fig. 3, device (1) keeps more A HA disk (2a to 2d).In specific example, and referring to Fig. 4, there are three parallel groove (203) (two sides for HA disk (201) tool Groove (203a and 203c) be 300 μm wide and 300 μm of depths；And intermediate groove (203b) (between grooves on two sides) is 500 μm Wide and 500 μm of depths).Intermediate groove is designed to more wider than the groove of two sides and deeper, so that HA disk can more easily be divided into two A identical half disk, for head to head omparison purpose.Fig. 5 is the signal of the wherein groove (2003) with biomembrane (2005) Property cross-sectional view.The PCT Patent Application PCT/ that the other datail description of HA disk is on September 9th, 2015 in international filing date In CN2015/089238.

Although not shown in FIG. 5, disk can be oriented so that retrogressing between interdental tooth in space (because It is easy to dental plaque for the position (in view of cleaning difficulty etc.).Only (clamping plate stores in humid conditions not subject during dining In transparent vessel) it takes out clamping plate and carries out dental hygiene procedures.And then, clamping plate is worn again.It is required that subject is when drinking Use suction pipe.

(c)Biology in situ film is discharged from HA table

All HA disks pass through tweezers after 48 hrs and remove from clamping plate.Using tweezers to keep the edge of HA chip and by HA Disk is transferred in the 2mL centrifuge tube for accommodating PBS (phosphate buffered saline (PBS)) solution.It is before the transfer of each disk that tweezers are thoroughly clear Wash (water；75% alcohol；And then deionized water).

(d)The preparation of toothpaste supernatant

15 grams of deionized waters are added in 5 grams of toothpaste (using any one of present composition embodiment 1 to 7, control Composition embodiment 8 to 10 or commercially available preparation are (for example, traditional Chinese medicine and TA preparation Yunnan Baiyao willow herb product, lot number 20190408F05 (" YNBY product ").Thoroughly after stirring, by mixture with 12,000RPM centrifugation 20 minutes.On the day before use It prepares supernatant and is stored at 4 DEG C.

(e)Confocal laser scanning microscope, CLSM

After clamping plate removal HA disk.Using HA disk for passing through the different present compositions and reference composition progress From outer processing.It is handled with target supernatant and (is such as described in PCT with microorganism fluorescence probe and stannous fluorescence probe label Announce WO2015/139263；In Shi et al.) after, pass through confocal laser scanning microscope, CLSM (" CLSM ") measurement (as described below) Biomembrane in groove.Preferably, stannous fluorescence probe is tert-butoxy-formamide, N- [3', 6'- bis- (diethylaminos)- 3- oxo spiral shell [1H- iso-indoles -1,9'- [9H] xanthene]-H)-yl] (being purchased from Chinese Shanghai Fudan University doctor Tao Yu).It is preferred that Ground, microorganism fluorescence probe are Molecular Probes^TM BacLight^TMSystem (is purchased from Thermo Fisher)。

(f)Disk prepares

HA disk rinses in PBS solution, and each HA disk is split into two halves by tweezers.Hereafter, each half disk is quiet State is placed in the PBS solution of 500 μ L to 1000 μ L 1 minute.It is handled each disk 2 minutes by PBS solution or toothpaste supernatant.It is logical It crosses and keeps each disk to clean each disk with tweezers, waggle ten is taken turns in the PBS solution of 1mL, and is then repeated this and washed Wash circulation.Then each disk static state is immersed into 500 μ L into 1000 μ L PBS solutions 5 minutes.

(g)Fluorescent staining and microexamination

It is reported thatBacLight^TMSystem is when assessing the bacterial action in natural plaque biofilm It is a kind of reliable alternative solution, wherein there are the bacteriums of several types.BacLight^TMFluorescence detection Bacterium is dyed into red or green according to its permeability of the membrane.The ratio of green/red and live/dead ratio are related well.When When analyzing antimicrobial activity, it is believed that live/dead colouring method is reliable.After processing and immersion, each half disk Sn probe It is dyed 30 minutes in the dark with Syto-9 probe (including 5 μM of Syto-9 and 5 μM of Sn probes), and the other half disk is used L7012Dye solution (containing 5 μM of Syto-9+30 μM of propidium iodides) dyes 15 minutes in the dark.Dye After color, each disk static state is immersed into 500 μ L into 1000 μ L PBS solutions 2 minutes.By keeping each disk with tweezers, in 1mL Waggle five is taken turns to wash disk again in PBS solution, and is repeated.For L7012The sample of dyeing Product, use following parameter: λ ex=488nm, λ em=500/635nm, 20X object lens, and from 60 μ of the bottom scan of surface bacteria M, wherein step-length=3 μm.For the sample of SYTO-9/Sn dyeing, following parameter: λ ex=488nm/543nm, λ em is used =500/580nm, 20X object lens, and from 60 μm of the bottom scan of surface bacteria, wherein step-length=3 μm.

(h)Confocal laser scanning microscope, CLSM

Use Leica^TMTCS SP8AOBS spectrum Laser Scanning Confocal Microscope.Confocal system is by Leica^TMDM6000B is vertical Microscope and Leica^TMThe vertical microscope composition of DMIRE2.Stand type support is used to be related to being slidably installed the application of sample；And have 37 DEG C of incubation rooms and CO₂The vertical racks for being enriched with attachment provide living cells application.Microscope shares a replaceable laser and sweeps Head is retouched, and other than the motor drive platform of themselves, there are one the high-precision Z platforms of galvanometer driving, this has Conducive to the fast imaging in focal plane (Z).Other than epi-fluorescence, microscope also supports a variety of transmitted light contrast methods, packet Bright field, polarised light and differential interference comparison degree are included, and equipped with 5x, 20x, 40x, 63x (oily and dry) and 100x (oil) Leica^TMObjective lens.

Describe laser scanning and detection system.There are four (one, laser for the supply of TCS SP2 AOBS confocal system Diode, an argon gas and two He-Ne lasers), therefore allow to excite the UV of electromagnetic spectrum, within the scope of visible and far infrared Various fluorescent dyes.Design (including the acousto-optic tunable filter (" AOTF "), acousto-optic beam splitter of laser scanning head (" AOBS ") and four prism spectrophotometer detectors) allow while exciting and detecting three kinds of fluorescent dyes.Vertical microscope is also With transmitted light detector, so that transmitted light images can be covered in fluorescence records.

Use Leica^TMConfocal software.Copolymerization is burnt via equipped with dual screen and operation Leica^TMConfocal The standard Pentium PC of software is controlled.Leica Confocal software is the acquisition of multidimensional image series, processing and analysis Interface is provided, including 3D reconstruction and measurement, physiology record and analysis, delay, fluorescent dye common location, photobleaching technology are such as FRAP and FRET, spectral mixing and polychrome reparation.About image analysis, L7012 is selectedDyeing Sample quantifies the ratio of red and green pixel, and selects the sample of SYTO-9/Sn dyeing red and green to quantify The overlapping efficiency of color pixel.Using the software, to the pixel of the pixel overlapping and " red " stannous probe of " green " bacterial probe Overlapping identified, and then by the value divided by all non-black pixels (the stannous probe including non-overlap) to provide bacterium The common location percentage of middle stannous.In general, the common location percentage is higher, stannous is delivered in bacterium more by oral care product Effectively.

As a result: with present composition embodiment 2 (i.e. Sn+0.50%TA), reference composition embodiment 9 (i.e. only Sn) and Commercially available YNBY product treatment subject.As a result it is provided in table 4.

Table 4- biofilm bacteria activity and active permeation

As a result it shows, contains antifibrinolysis agent (for example, tranexamic acid) and antibacterial agent (for example, stannous ion source) Present composition embodiment 2 effectively improve the reduction (55.00% killing bacteria) of bacterial activity, and for containing anti- Microbial inoculum and stannous but killing bacteria (46.39%) is reduced without containing the reference composition embodiment 10 of tranexamic acid.It is commercially available YNBY product shows comparable killing bacteria (47.86%) relative to reference composition embodiment 9.

The result shows that present composition embodiment 2 (82.29%) is relative to reference composition embodiment 9 (61.48%) With the significant higher stannous common location percentage of YNBY product (2.25%).As a result TA, which is also shown, will not damage as by Sn weight The stannous release efficiency of coefficient measurement is folded, wherein present composition embodiment 2 (0.9301) and reference composition embodiment 9 (0.9206) Sn overlap coefficient is essentially similar.In fact, the data are supported to work as with antifibrinolysis agent (for example, ammonia First naphthenic acid) combination when, with compare and commercially available preparation compared with, improve infiltration of the stannous ion into biomembrane.

C: for measuring the measuring method of the improved wound healing of people's gingival fibroblasts

It is cured with assessing with wound after the present composition and reference composition processing using external people's gingival fibroblasts Close the influence of migration.This method includes three phases:

The primary people's gingival fibroblasts of 1st stage-culture (" HGF ")

Patient collector gingival fibroblasts are extracted from tooth and are washed with the PBS of 5mL (phosphate buffered saline (PBS)).It will Tissue, which is cut into small pieces, to be placed in 15mL centrifuge tube.By 8% dispase of 1mL of sample equivalent and 6% clostridiopetidase A of 1mL 37 It is digested 1 hour at DEG C, needs every 15 minutes shake samples during this period.Once digestion process complete, by pipe at room temperature with 1100RPM is centrifuged 6 minutes.After centrifugation, cell precipitation is formed in the bottom of pipe, separates them with upper solution.Then it abandons It removes supernatant, and cell precipitation is suspended in the fresh minimum essential medium of 3mL (" MEM " is purchased from Thermo Fisher) In culture medium, it is then transferred into culture dish.Culture dish with cell is placed in 37 DEG C and 5%CO₂Incubator in about 10 It.The culture medium color change of every two days inspection culture dishes.In case of culture medium color change, then fresh culture is replaced.

2nd stage-subculture people's gingival fibroblasts

When the cell monolayer coverage rate of culture dish is 80% to 90%, removes basal culture medium and washed with the PBS of 5mL. 0.25% trypsin-EDTA solutions of 1mL are added, and cell is stood to about 1 minute to 2 minutes at 37 DEG C, until cell In obvious circle.Culture dish may be needed to pat to remove any sticky cell from culture dish surface.It is fresh that at least 1mL is added Cell is collected into 15mL centrifuge tube by MEM culture medium with inactivating trypsase.Then it will manage at room temperature with 1100RPM Centrifugation 6 minutes.Liquid is discarded supernatant, and in the fresh MEM culture medium of the 4mL that cell precipitation is resuspended in same centrifuge tube.By 4 A culture dish and 1mL cell suspending liquid and the fresh MEM culture medium of 9mL are respectively placed in 37 DEG C and 5%CO₂Incubator in about 3 to 5 It, until observing on culture dish 80% to 90% cell monolayer covering.Before wound healing measurement, which should be repeated 2 to 4 times, to obtain highest cell viability.

3rd stage-wound healing analysis

When the cell monolayer coverage rate on culture dish is 80% to 90%, removes basal culture medium and washed with the PBS of 5mL It washs.0.25% trypsin-EDTA solutions of 1mL are added, and cell is stood to about 1 minute to 2 minutes at 37 DEG C, until Cell is in obvious round.Culture culture dish may be needed to pat to remove any sticky cell from culture dish surface.It is added at least Cell is collected into 15mL centrifuge tube by the fresh MEM culture medium of 1mL with inactivating trypsase.Then will pipe at room temperature with 1100RPM is centrifuged 6 minutes.Liquid is discarded supernatant, and cell precipitation is resuspended in the fresh MEM culture medium of 6mL.By 1mL cell Suspension and the fresh MEM culture medium of 1mL are added separately in each hole of 6 orifice plates.By plate in 37 DEG C and 5%CO₂It is lower to incubate directly To the cell monolayer covering for forming 50% to 70%.Then the exterior base in hole is labeled as to intermediate line during Image Acquisition As reference line.By the right half part of cell monolayer being scraped with the 1mL pipette tip of sterilizing come manual creation wound.With 2mL PBS washs cell to remove the cell of any suspension until can't see the cell of suspension.Xiang Kongzhong be added 2mL culture medium and 2ml culture medium containing 1% reference composition or the 2mL culture medium containing 1% present composition.

Using havingUIS2 WHN10X object lensIX71 digital single-lens reflex camera shoots HGF High-density digital image.By using the intermediate wire tag on plate as reference line, first was obtained at 0 hour (that is, baseline) Image.Then by plate in 37 DEG C and 5%CO₂It is lower to incubate different time intervals, as described below.As previously obtained matched shooting Region, and the time interval later (for example, 16 hours, 24 hours, 48 hours, 65 hours, 72 hours etc.) after baseline obtains Take image to assess cell coverage rate (%) as the wound healing performance shown under different disposal branch.Pass through WimScratch software (being purchased from Wimasis GmbH, Germany) assessment image is with the determining matching baseline chart with each sample As the degree (that is, percentage) compared to HGF cell covering (that is, wound healing) by the wound boundaries of label, shown in dotted line. WimScratch software is covered using advanced edge detection and soverlay technique identification cell and white space, i.e. green in image Lid figure represents cell overlay area and the gray area (black of such as Fig. 6 of specific image (as shown in the gray area in Fig. 6) Shown in region) indicate wound area.Reading is presented on two regions, and is standardized as the percentage of the gross area.

As a result: Fig. 6 is shown with present composition embodiment 2 (i.e. Sn+0.50%TA) or reference composition embodiment 9 24 hours HGF images after (only Sn) processing.Referring to Fig. 6, as a result show containing antifibrinolysis agent and antibacterial agent (example Such as, stannous ion source) present composition embodiment 2 relative to the lower thin of the HGF handled with reference composition embodiment 9 Born of the same parents' coverage rate (total -50% baseline of coverage rate of 3.3%=53.3%) is covered effectively by cell increased after obvious wound Improve wound healing (by dashed lines labeled) (total -50% baseline of coverage rate of 22.4%=72.4%).

D: mouthrinse composition

As embodiment 11 to 14 shows mouthrinse composition according to the present invention in the following table 5.These compositions contain Asia Stannous ion source and antifibrinolysis agent.Preferably, these compositions and the commercially available preparation without these ingredients Compared to showing improved gums healthy beneficial effect.

Table 5: mouthwash formulations

Dimension disclosed herein and value are not understood as being strictly limited to cited exact numerical.On the contrary, unless in addition It indicates, otherwise each such dimension is intended to indicate that described value and the range functionally equivalent around the value.For example, being disclosed as The dimension of " 40mm " is intended to indicate that " about 40mm ".

It limits unless expressly excluded or in other ways, each document cited herein, including any cross reference Or related patents or patent application and the application is claimed priority to it or any patent application or patent of its advantages, It is incorporated by reference and is incorporated herein accordingly.Reference to any document be not to its as with it is of the invention any disclosed Or the approval of the claimed prior art herein, or be not to its own or with any one or more with reference to text Combination proposition, suggestion or the approval for disclosing any such invention offered.In addition, when any meaning or definition of term in the present invention With any meaning of same term in document incorporated by reference or when defining contradiction, it should obey and assign in the present invention The meaning or definition of the term.

It limits unless expressly excluded or in other ways, each document cited herein, including any cross reference Or related patents or patent application and the application is claimed priority to it or any patent application or patent of its advantages, It is incorporated by reference and is incorporated herein accordingly.Reference to any document be not to its as with it is of the invention any disclosed Or the approval of the claimed prior art herein, or be not to its own or with any one or more with reference to text Combination proposition, suggestion or the approval for disclosing any such invention offered.In addition, when any meaning or definition of term in the present invention With any meaning of same term in document incorporated by reference or when defining contradiction, it should obey and assign in the present invention The meaning or definition of the term.

Although specific embodiments of the present invention have had been illustrated and described, to those skilled in the art It is readily apparent that a number of other change and modification can be made without departing from the spirit and scope of the present invention.Therefore, It is intended to all such changes and modifications for covering in appended claims and belonging in the scope of the invention.

Claims (17)

1. a kind of oral care composition, the oral care composition includes:

A) 0.01% to 5% stannous ion source by weight of the composition；And

B) 0.01% to 10% antifibrinolysis agent by weight of the composition.

2. oral care composition according to claim 1, wherein the antifibrinolysis agent is the chemical combination of formula (I) Object:

H₂N-X-COOH (I)

Wherein X is branch or non-branched, saturated or unsaturated aliphatic group；Or aromatic group.

3. according to claim 1 or oral care composition as claimed in claim 2, wherein the antifibrinolysis agent with By weight of the composition less than 5%, preferably less than 3%, and even more preferably less than 1% amount exists, and excellent Selection of land is selected from tranexamic acid, ε aminocaproic acid, p-aminomethylbenzoic acid or their combination.

4. oral care composition according to claim 3, wherein the antifibrinolysis agent is tranexamic acid, it is excellent Selection of land is with by weight of the composition 0.1% to less than 1%, or more preferably 0.2% to 0.7% amount exists.

5. a kind of oral care composition, the oral care composition includes:

A) 0.01% to 5% stannous ion source by weight of the composition；And

B) 0.01% to 10% one or more compounds by weight of the composition, one or more compounds Selected from tranexamic acid, ε aminocaproic acid, p-aminomethylbenzoic acid and their combination.

6. oral care composition according to any one of the preceding claims, wherein the stannous ion source is by described The poidometer 0.05% to 4% of composition, or preferably 0.1% to 2% amount exist, and sub- selected from stannous chloride, fluorination Tin, stannous acetate, gluconic acid stannous, stannous oxalate, stannous sulfate, lactic acid stannous, stannous tartrate, stannous iodide, chlorine fluorine Change stannous, hexafluoro zirconate stannous, stannous citrate, stannous malate, glycine stannous, carbonic acid stannous, phosphoric acid stannous chloride, pyrophosphoric acid Stannous, metaphosphoric acid stannous and their combination.

7. oral care composition according to any one of the preceding claims, the oral care composition also includes to press The thickener of the poidometer 0.01% to 5% of the composition, the thickener includes at least one reagent selected from the following, excellent At least two reagent of selection of land:

(i) linear sulphated polysaccharide；

(ii) natural gum；

(iii) non-ionic cellulose or derivatives thereof；

(iv) polyvinylpyrrolidone (PVP)；

(v) polymer of more carboxylated vinyl main chains is included at least；

(vi) polyacrylamide；

(vii) comprising the copolymer of acrylamide；

(viii) pectin；

(ix) protein；

(x) polyethylene glycol (PEG), preferably high molecular weight PEGs；And

(xi) their combination.

8. oral care composition according to claim 7, wherein the thickener is preferably by the composition The amount of poidometer 1% to 2.5% exists, in which:

(i) the linear sulphated polysaccharide is carrageenan；

(ii) natural gum is selected from xanthan gum, karaya gum, gum arabic, bassora gum and their combination；

(iii) described non-ionic cellulose or derivatives thereof, described non-ionic cellulose or derivatives thereof have 50,000 Average molecular weight within the scope of Er Dun to 1,300,000 dalton and preferably 300 to 4,800 average degree of polymerization；

(iv) more carboxylated vinyl main chains and the polymer selected from the following: maleic anhydride and methyl vinyl ether are included at least Copolymer, the copolymer have 30,000 dalton to 1,000,000 dalton molecular weight；The homopolymer of acrylic acid； And the copolymer of maleic acid and acrylic or methacrylic acid；And

(v) their combination.

9. oral care composition according to claim 8, in which:

(i) carrageenan is selected from kappa carrageenan, ι-carrageenan, λ-carrageenan and their combination；

(ii) natural gum is xanthan gum；

(iii) described non-ionic cellulose or derivatives thereof is hydroxyethyl cellulose (HEC)；

It (iv) is maleic acid or maleic anhydride and methyl vinyl ether including at least the polymer of more carboxylated vinyl main chains Copolymer；And

(v) their combination.

10. oral care composition according to any one of the preceding claims, the oral care composition also include 0% to less than 0.001% folic acid by weight of the composition, or preferably free or substantially free of folic acid.

11. oral care composition according to any one of the preceding claims, the oral care composition also includes: By weight of the composition 0.01% to 5%, preferably 0.1% to 2% seasoning composition, wherein the flavoring agent Composition includes:

(i) flavouring mixture, the flavouring mixture include greater than 0% based on the weight of the seasoning composition to small In 55% or the gaultherolin greater than 65% to 95%；Based on the weight of the seasoning composition be greater than 0% to less than 30% or the menthol greater than 35% to 65%；It is greater than 0% to less than 1% or big based on the weight of the seasoning composition In 5% to 50% eugenol；And greater than 0% to less than 3% or greater than 8% based on the weight of the seasoning composition To 30% cineole；Or

(ii) free or substantially free of gaultherolin, menthol, eugenol and the flavouring mixture of cineole.

12. oral care composition according to any one of the preceding claims, the oral care composition also include By weight of the composition 0.0025% to 2%, or preferably 0.5% to 1.5% fluoride sources, wherein the fluorine from Component is preferably chosen from sodium fluoride, indium, amine fluoride, sodium monofluorophosphate (MFP), potassium fluoride, zinc fluoride and their group It closes.

13. oral care composition according to any one of the preceding claims, the oral care composition also include By weight of the composition 10% to 70%, or preferably 15% to 30% total water content；The more preferably described oral cavity Care composition is Dentrifice composition.

14. oral care composition according to any one of the preceding claims, wherein the composition has 4.5 to 11 PH, or preferably 5 to 10 pH.

15. a kind of method for the gums healthy for promoting people experimenter, the method includes the oral administration roots to the subject According to oral care composition described in any one of claims 1 to 14, preferably once a day, more preferably twice daily.

16. according to the method for claim 15, wherein the promotion gums healthy occurred within period selected from the following:

A) 0 hour to 72 hours；

B) 0 hour to 48 hours；

C) 0 hour to 24 hours；

Wherein 0 hour is when applying the oral care composition.

17. method according to claim 15 or 16, wherein gums healthy is selected from:

(i) improve the gums wound healing in the oral cavity；

(ii) improve the reduction of the bacterial activity in the oral cavity；Or

(iii) their combination.