CN1320879C - Oral preparation system - Google Patents

Abstract

An oral preparation of the present invention contains a multi-composition system including a calcium ion supplying compound; a fluoride ion supplying compound;a polyolphosphate ion supplying compound; and a monofluorophosphate ion supplying compound, wherein the calcium ion supplying compound and the fluoride ion supplying compound are separated within the oral preparation.

Description

Oral preparation system

technical field

The present invention relates to an oral formulation system comprising a calcium ion-donating compound and a fluoride ion-donating compound.

Background technique

The main component of tooth enamel is hydroxyapatite, and the loss of phosphate ions or calcium ions from teeth in the mouth (i.e., demineralization) and the crystallization of calcium phosphate or hydroxyapatite (i.e., remineralization) are usually between A state of balance. Fluoride ions are able to prevent dental caries by inhibiting demineralization and promoting the replenishment and crystallization of calcium and phosphate ions, ie remineralization of teeth.

However, when fluoride ions and calcium ions are mixed in the same composition, calcium fluoride precipitates in the composition. This preformed calcium fluoride is a powdery substance (average particle size: several microns), and when it is used in the oral cavity, it is hardly adsorbed to the teeth because the particle size is too large, so it is difficult to promote tooth remineralization role.

Based on this, an oral preparation has been proposed in which the calcium ion source and the fluoride ion source are made into separate compositions, and then the two compositions are mixed with each other in the oral cavity, or mixed immediately before being introduced into the oral cavity, Calcium fluoride is thus formed in the mouth. For example, there is an oral hygiene product containing a calcium ion source, a fluoride ion source and a calcium masking agent (JP-A-58-219107 and JP-A-10-511956). However, since this oral hygiene product contains a calcium-masking agent, this oral-hygiene product has a problem in that the adsorption of fluorine to the teeth is instead inhibited by the calcium-masking agent.

In addition, a composition containing calcium fluoride preformed in a colloidal form has also been proposed (JP-A-3-72415). However, it has a problem that the stability of the colloid decreases during long-term storage, so that its effect is insufficient to deposit calcium fluoride particles on the tooth surface.

Japanese Patent Laid-Open No. 63-101312 discloses that rapid precipitation of calcium fluoride can be induced. Even so, however, it is impossible to control the aggregation rate of calcium fluoride particles (primary particles) after precipitation so that after the formation of primary particles, the same homo-aggregation proceeds rapidly to form secondary particles. The problem with the secondary particles of calcium fluoride thus formed is that the particle size grows too large, reducing the amount of adsorption on teeth.

It should be noted here that the primary particles are calcium fluoride crystal particles formed of fluoride ions and calcium ions, and the secondary particles are particles formed by aggregation, for example, the same aggregation of primary particles.

In addition, JP-A-10-511956 discloses the control of fluoride formation in mouthwashes, dentifrices and gels. That is, to control the formation of calcium fluoride, it is proposed to include a calcium fluoride inhibitor that causes a delay in the precipitation of calcium fluoride for at least about 5 seconds after mixing of calcium ions and fluoride ions.

The inclusion of the calcium fluoride inhibitor results in a delay in the aggregation (ie formation of secondary particles) of calcium fluoride. However, the presence of this inhibitor also suppresses the formation reaction of calcium fluoride (ie, the formation of primary particles), which causes a problem that the amount of formation of calcium fluoride as primary particles decreases.

Therefore, in order to achieve a more effective promotion of remineralization, it is desirable that the rate of calcium fluoride aggregation (formation of secondary particles) can be controlled without affecting calcium fluoride formation (formation of primary particles).

Contents of the invention

The present invention provides an oral preparation system comprising the following components:

(A) compounds providing calcium ions;

(B) compounds that donate fluoride ions but do not donate monofluorophosphate ions;

(C) a compound that provides polyolphosphate ions; and

(D) a compound providing monofluorophosphate ion (monofluorophosphate ion),

Wherein components (A) and (B) are separated in the oral preparation system.

The present invention also provides a multi-component oral preparation system, which is characterized in that it comprises the following components:

(B) compounds donating fluoride ions but not monofluorophosphate ions,

(D) a compound providing a monofluorophosphate ion,

(E) Polyhydroxycalcium Phosphate

Wherein components (B) and (E) are separated in the oral preparation system.

The present invention also provides an oral preparation containing a multi-composition system comprising composition (X) and composition (Y), characterized in that component (C) is mixed in the multi-composition system:

(X) a first composition comprising (A) and (D);

(Y) a second composition comprising (B);

(A) compounds providing calcium ions;

(B) compounds that donate fluoride ions;

(C) a compound that provides polyhydroxyphosphate ions; and

(D) Compounds that donate monofluorophosphate ions.

Brief description of the drawings

FIG. 1 shows the change in turbidity of the solution after mixing compositions X and Y in one example and a comparative example.

FIG. 2 shows the state of adsorption on HAP powder in Example 1. FIG.

FIG. 3 shows the state of adsorption on HAP powder in Comparative Example 1. FIG.

FIG. 4 shows the state of adsorption on HAP powder in Comparative Example 3. FIG.

Fig. 5 shows the results of X-ray diffraction measurement of calcium fluoride crystal size.

Figure 6 shows the pH change caused by HAP titration in one and comparative examples.

Figure 7 shows the state of an incipient caries segment.

Figure 8(a) shows a CMR (soft X-ray) photograph of this tooth.

Figure 8(b) shows the mineral recovery ratio for one example and a comparative example.

Detailed ways

The present invention provides an oral preparation system capable of forming calcium fluoride primary particles and controlling the rate of calcium fluoride aggregation (i.e. formation of secondary particles), and thus allowing more adsorption of calcium fluoride particles on teeth etc. , which is excellent in inhibiting tooth demineralization and promoting remineralization.

The present inventors have found that polyhydroxyphosphate ions can control calcium fluoride secondary particles (fluorine Calcium chloride aggregates) particle size, thereby obtaining the benefits of the present invention.

That is, the present inventors prepared an oral preparation system capable of promoting the formation of primary particles and capable of controlling the formation of secondary particles, thus exhibiting inhibition of tooth demineralization and promotion of remineralization by applying this oral preparation system Excellent effect, this oral preparation system, as an oral preparation, is a multi-composition system containing (A) a compound that provides calcium ions and (B) a composition that provides fluoride ions but does not provide monofluorophosphate ions, Wherein components (A) and (B) are separated, in other words, they are not in contact with each other in the oral preparation system. The multi-composition system further contains (C) a polyhydroxyphosphate ion-donating compound and (D) a monofluorophosphate ion-donating compound contained as components in either component (A) or component (B) containing In the composition, or in both the composition containing component (A) and the composition containing component (B), or in another separate composition.

Moreover, the present inventors have made it possible to rapidly produce calcium fluoride fine particles (primary particles) by mixing components (A), components (B), components (C) and components (D) with each other, such as in multi-combination Prepare any of the following combinations in the physical system:

(1) Compositions comprising components (A), (C) and (D), and combinations of individual compositions comprising component (B);

(2) Compositions containing component (A), and combinations of separate compositions containing components (B), (C) and (D);

(3) a combination of a composition comprising components (A) and (C) and a separate composition comprising components (B) and (D);

(4) Compositions comprising components (A) and (D), and combinations of separate compositions comprising components (B) and (C);

(5) Compositions comprising components (A) and (D), and combinations of separate compositions comprising (B) and separate compositions comprising (C);

(6) Compositions comprising components (A) and (C), a single composition comprising component (B), and a combination of a single composition comprising component (D);

(7) Compositions comprising components (B) and (D), a single composition comprising component (A), and a combination of a single composition comprising component (C);

(8) a combination of a composition comprising components (B) and (C), a single composition comprising component (A), and a single composition comprising component (D); and

(9) A combination of a composition containing component (A), a single composition containing component (B), a single composition containing component (C), and a single composition containing component (D).

The primary particle size of the calcium fluoride microparticles is preferably 0.3 to 15 nm (nanometer), more preferably 0.3 to 12 nm, further preferably 0.3 to 9 nm.

The secondary particles which are aggregates of calcium fluoride fine particles may contain monofluorophosphate. The content range of monofluorophosphate is preferably 0.05 to 20 wt.% (weight percentage) of the aggregate, more preferably 0.1 to 15 wt.% of the aggregate, further preferably 0.5 to 10 wt.% of the aggregate.

The secondary particles of the calcium fluoride fine particles may contain polyhydroxyphosphate. The content range of polyhydroxyphosphate is preferably 0.05 to 20 wt.% of the aggregate, more preferably 0.1 to 15 wt.% of the aggregate, further preferably 0.5 to 10 wt.% of the aggregate.

Further, the secondary particle of the calcium fluoride microparticles may contain both monofluorophosphate and polyhydroxyphosphate, and it may be a composite particle of monofluorophosphate and polyhydroxyphosphate. The total content of monofluorophosphate and polyhydroxyphosphate is preferably 0.1 to 40 wt.% of the composite particles, more preferably 0.2 to 30 wt.%, even more preferably 1 to 20 wt.% of the composite particles.

Regarding the use of the oral preparation system of the present invention, since more calcium fluoride primary particles can be formed and the rate of calcium fluoride aggregation (secondary particle formation) can be controlled, more calcium fluoride particles can be adsorbed on teeth and the like. Therefore, the oral preparation system provided by the present invention has excellent adsorption capacity on surfaces such as teeth in the oral cavity, and excellent effects of inhibiting demineralization and promoting tooth remineralization.

In addition, using the oral preparation system of the present invention containing polyhydroxyphosphate as a component of the multi-composition system, when calcium fluoride secondary particles are formed, calcium fluoride fine particles and polyhydroxyphosphate easily form composite particles. in the secondary particle. The oral preparation system can suppress the reduction of residual plaque pH (in particular, the residual plaque after brushing) by the pH buffering ability of the polyhydroxyphosphate contained in the composite particles, thereby preventing resulting in dental caries. Further, in one embodiment, calcium fluoride particles and monofluorophosphate form composite particles, and then such composite particles are present in secondary particles in which the effect of this monofluorophosphate is improved, i.e. , enhance the effect of inhibiting tooth demineralization and promoting tooth remineralization. These effects are similar to the advantages of caries prevention.

When the oral preparation system of the present invention is used, the calcium fluoride can be effectively adsorbed on the teeth by controlling the particle size of the calcium fluoride, thereby obtaining excellent effects of inhibiting demineralization and promoting tooth remineralization.

Further, in one embodiment, calcium fluoride microparticles, monofluorophosphate and polyhydroxyphosphate form a composite particle, and then the composite particle exists in the secondary particle, and through the synergistic effect between them, the pH of the residual plaque Decline is suppressed, demineralization of teeth is suppressed, remineralization is promoted more effectively, and thus caries can be more effectively prevented.

Examples of calcium ion-donating compounds that can be used as component (A) in the present invention include polyhydroxy calcium phosphate, calcium hydroxide, calcium chloride, calcium acetate, calcium formate, calcium lactate, calcium nitrate, calcium gluconate , Calcium Benzoate, Calcium Isobutyrate, Calcium Propionate, Calcium Salicylate, Calcium Carbonate, Calcium Hydrogen Phosphate, Calcium Phosphate, Hydroxyapatite and mixtures thereof. Examples of polyhydroxy calcium phosphate (component (E)) include calcium glycerophosphate, calcium glucose-1-phosphate and calcium glucose-6-phosphate. Examples of preferred calcium ion-donating compounds for improving the taste of the oral preparation system are calcium lactate and calcium glycerophosphate.

In order to effectively form calcium fluoride in the oral cavity, the compound providing calcium ions in component (A) preferably provides 10 to 16000 ppm calcium ions, more preferably 50 to 12000 ppm calcium ions, and further Preferably it is 200 to 8000 ppm calcium ions. As the calcium ion-donating compound usable in the present invention, a calcium-donating compound capable of being ionized is preferably used. The composition containing component (A) and the use amount of the composition containing component (B) are equal in weight, and the amount of this calcium ion-providing compound in the composition containing component (A) is preferably It is in the range of 0.25 to 400 μmol/g (micromol/g), more preferably in the range of 1.25 to 300 μmol/g, and still more preferably in the range of 5 to 200 μmol/g.

Examples of fluoride ion-donating compounds useful as component (B) in the present invention include sodium fluoride, stannous fluoride, potassium fluoride, zinc fluoride, betaine fluoride, alanine fluoride Tin, sodium fluorosilicate, hexylamine fluoride and mixtures thereof. Examples of preferred fluoride ion donating compounds are sodium fluoride and stannous fluoride.

In order to effectively form calcium fluoride in the oral cavity, the compound providing fluoride ions in component (B) preferably provides the composition containing component (B) from 5 to 4000 ppm fluoride ions, more preferably from 25 to 2000 ppm, further Preferably it is 100 to 1000 ppm. In order to make the fluoride ion concentration in the above range, if component (A) and component (B) are equal in weight, for example, in the composition containing component (B), the compound providing fluoride ion preferably contains The amount ranges from 0.065 to 210 μmol/g, more preferably from 0.325 to 158 μmol/g, further preferably from 2.6 to 105 μmol/g.

Calcium ions and fluoride ions react at a ratio of 1:2 (molar ratio) to form calcium fluoride. In order to effectively form calcium fluoride in use, the content ratio (molar ratio) range of the compound (expressed by calcium) providing calcium ion and the compound (expressed by fluorine) providing fluoride ion in the oral preparation system of the present invention is preferably 1:8 to 4:1, more preferably 1:4 to 2:1.

Examples of the monofluorophosphate ion-donating compound usable as component (D) in the present invention include sodium monofluorophosphate, potassium monofluorophosphate, magnesium monofluorophosphate, calcium monofluorophosphate. A preferred compound providing monofluorophosphate ions is sodium monofluorophosphate. Monofluorophosphate ions remain in the oral cavity, especially in dental plaque, etc., and are gradually decomposed by phosphatase, etc. in saliva or dental plaque, thereby continuously supplying dental fluoride ions. If component (D) is contained only in the composition containing component (A), and the use amount of the composition containing component (A) and the composition containing component (B) is equal on weight, The monofluorophosphate ion in the composition containing component (A) is preferably in an amount of 0.065 to 210 μmol/g, more preferably 0.325 to 158 μmol/g, further preferably 2.6 to 105 μmol/g.

The compound providing monofluorophosphate ion as component (D) may be contained in the composition containing the above-mentioned component (A) or the above-mentioned component (B), may be contained in the composition containing the component (A) , may be included in both compositions of component (B), or may be included as a third component independently of the composition containing components (A) and (B), or may be included as one component in the second in three compositions.

Examples of polyhydroxyphosphate ion-donating compounds that can be used as component (C) in the present invention include monosaccharides containing 3 to 10 carbon atoms and having one or more phosphate groups per molecule, consisting of 2 Oligosaccharides consisting of up to six such monosaccharides and polyols containing from 3 to 10 carbon atoms and having one or more phosphate groups per molecule. Specific examples of compounds that donate polyhydroxyphosphate ions include glycerophosphate, glyceraldehyde 3-phosphate, erythrose 4-phosphate, ribose 5-phosphate, glucose 1-phosphate, glucose 6-phosphate, inositol Monophosphate, Phytate, Fructose 1-phosphate, Fructose 6-phosphate, Fructose 1,6-diphosphate, Ascorbic acid 2-phosphate, Phosphorylated maltotriose, Phosphorylated maltotetraose and their salts such as sodium, potassium, calcium, or magnesium salts. Among them, sodium salt or calcium salt of glycerophosphate, glucose 1-phosphate, or glucose 6-phosphate are preferable. As mentioned above, in the case of containing polyhydroxy calcium phosphate (component (E)), such as calcium glycerophosphate, calcium glucose-1-phosphate and calcium glucose-6-phosphate, it can also act as a calcium ion donating compound (component (E) points (A)).

A compound providing polyhydroxyphosphate ions as component (C) may be contained in a composition containing the above-mentioned component (A) or the above-mentioned component (B), may be contained in a composition containing component (A), Contained in both compositions of component (B), or may be included as a third component independently of the composition containing component (A) and component (B), or contained as a component in a third composition.

In the oral preparation system of the present invention, the amount of the compound providing polyhydroxyphosphate ions as component (C) is preferably 0.125 to 200 μmol/g (micromol/g), more preferably 0.625 to 150 μmol/g, further preferably 2.5 to 100 μmol/g. When the polyhydroxyphosphate ion-providing compound is included as component (C) in a composition containing component (A), and the composition containing component (A) and the composition containing component (B) The amount of this polyhydroxyphosphate ion-donating compound in the composition containing component (A) is preferably 0.25 to 400 μmol/g, more preferably 1.25 to 300 μmol/g, when the amount used is equal in weight , and more preferably 5 to 200 μmol/g.

When polyhydroxycalcium phosphate (component (E)) is used simultaneously as a polyhydroxyphosphate ion-providing compound and a calcium ion-providing compound, and the composition containing component (E) and the composition containing component (B) When the amount of the composition used is equal in weight, the amount of such polyhydroxycalcium phosphate in the composition containing component (E) is preferably 0.25 to 400 μmol/g (micromol/g), more preferably 1.25 to 300 μmol/g, more preferably 5 to 200 μmol/g.

The oral preparation system of the present invention preferably uses sugar alcohol in the mixture at a concentration of 10 to 70 wt.%. Examples of sugar alcohols include lactitol, isomalt, maltotriitol, isomaltotriitol, panitol, isomaltotetraitol, erythritol, arabitol, ribitol, xylitol, sorbitol, mannitol, maltitol and the like. Such sugar alcohols may be in the D or L configuration, or mixtures thereof.

In addition, the sugar alcohol preferably contains xylitol, and the content of xylitol in the sugar alcohol is preferably 1 to 40 wt.%, more preferably 2 to 20 wt.%.

In the oral preparation system of the present invention, component (A) and component (B) are preferably placed in one container or multiple containers so that component (A) and component (B) do not contact each other, and Allow them to mix in the mouth, or mix immediately before introducing into the mouth.

In addition, the oral preparation system of the present invention is preferably a multi-composition system by maintaining component (A) and component (B) and the composition containing component (A) and the composition containing component (B) The composition is in a non-contact state until or just before use.

In order to form this multi-component system, component (A) and component (B) can be placed in different containers for each component, or component (A) and component (B) can be placed in a non-contact state. into a container. Examples of containers that are placed in a non-contact state include a tube that is divided inside by a partition into which another tube is inserted, and a container that is made by connecting separate tubes so that the opening of the container combine the contents.

The oral preparation system of the present invention can be mixed with anionic surfactants commonly used in oral preparation systems, for example, ester salts of alkyl sulfates, such as sodium lauryl sulfate, salts of N-acyl amino acids, such as N- Acyl sarcosinates, etc. In addition, ingredients commonly used in oral preparations can be added to the oral preparation system of the present invention, and examples of such ingredients include: abrasives such as silicic anhydride, calcium hydrogen phosphate and calcium carbonate; wetting agents such as glycerin and polyethylene glycol; Glycols; foaming agents; binders, such as sodium carboxymethylcellulose and carrageenan; sweeteners, such as sodium sucrose; coloring agents; preservatives, such as methylparaben; fungicides, such as benzene Sochloramine, triclosan, and propylcresol; anti-inflammatory agents, such as beta-glycyrrhizinate and tocopherol; fragrances, etc. These ingredients can be present in both the composition containing component (A) and the composition containing component (B), or in the composition containing component (A) or the composition containing component (B). .

The oral preparation system of the present invention can be used as, for example, tooth powder, lubricating dentifrice, toothpaste, liquid dentifrice, mouthwash and the like.

Example

The following examples further describe and demonstrate embodiments of the invention. The examples given are for illustration only and do not limit the invention.

1. Mouthwash

(1) Preparation of mouthwash

In each of the Examples and Comparative Examples, two components, Component (X) and Component (Y), were prepared according to the compositions shown in Table 1. Then, each of them is placed in a separate container for each component by the same weight.

(2) Measurement method

a. Observations on the adsorption status of particles on hydroxyapatite (HAP)

Composition (X) and composition (Y) in each of Examples and Comparative Examples shown in Table 1 were mixed in equal amounts. 10 g of HAP powder (available from Wako Pure Chemical Industries) was treated in 1 L of the prepared mixture for 3 minutes, washed with deionized water, and dried by vacuum drying, thus obtaining a powder. The status of calcium fluoride adsorption on the recovered HAP powder was observed by scanning electron microscopy (SEM).

The HAP powder sample on which calcium fluoride was adsorbed well was evaluated as "○", the HAP powder sample on which calcium fluoride was adsorbed somewhat was evaluated as "△" and the HAP powder sample on which calcium fluoride was little or not adsorbed The evaluation was "x".

Table 1

components Composition (wt.%) Example Comparative Example 1 2 1 2 3 x Y x Y x Y x Y x Y calcium glycerophosphate A, C (=E) 1 - 0.5 - - - 1 - - - calcium lactate A - - 0.5 - 1 - - - - - sodium monofluorophosphate D 0.7 - 0.7 - - - - - 0.7 - sodium fluoride B - 0.2 - 0.2 - 0.2 - 0.2 - 0.2 pure water ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 ^* 1 total 100 100 100 100 100 100 100 100 100 100 About the state of particle adsorption ○ ○ △ △ × Fluorine adsorption amount (mg/m ² ) 33 28 20 14 2

^* 1: balanced

b. Quantitative determination of fluorine adsorption on HAP pellets

In each example and comparative example, HAP pellets (APP-100; 10×10×2 mm, PENTAX, Japan) were treated in 10 ml of composition (X) for 30 seconds, and then in 10 ml of composition (Y) Process for 30 seconds. These treatments were alternated for 3 minutes. The calcium fluoride particles adsorbed on the surface of the HAP pellets by such treatment were extracted with hydrochloric acid. The amount of fluorine adsorbed on the surface of the HAP pellets was measured using the extract by an ion analyzer (Expandable ion Analyzer EA940, manufactured by ORION) equipped with a fluoride ion selective electrode (inplus-Fluoride ORION).

c. Potentiometric titration

0.1 g of HAP powder (control) and the HAP powders processed respectively by the compositions of Example 1 and Comparative Example 1 shown in Table 1 were accurately weighed, and 40 ml of deionized water was added to them, thereby preparing a suspension state slurry. Use automatic potentiometric titrator AT-300 (manufactured by Kyoto Electronics Manufacturing Company), the hydrochloric acid of 0.1N is added dropwise in this suspension with 0.5ml, 0.5ml, stirs continuously with agitator simultaneously, measures pH after dropping 5 minutes each time, obtains Titration curve.

d. Determination of calcium fluoride primary particle size

For the HAP powder (control) and the HAP powder samples treated separately by the compositions of Example 1 and Comparative Example 1 shown in Table 1, the 2-theta (2θ) degree was in the range of 2.5 to 75 by powder X-ray diffraction method. (Instrument: RINT2500VPC (manufactured by Riguka Corporation), Cu K-α, 40Kv, 120mA, divergence slit: 1 degree, divergence vertical restriction slit: 10mm, diffraction slit: 1.25 mm, receiver slit: 0.3mm, scan rate: 1.000 deg/min).

e. Component analysis of calcium fluoride secondary particles

The HAP powder samples treated by the composition of Example 1 shown in Table 1 were subjected to deposition treatment by Pt-Pd and used as measurement samples for EDS. Measurement of SEM-EDS (Energy Dispersive X-ray Analysis Method) (Instrument: S-4000 (manufactured by Hitachi Corporation) Under the condition of electron beam 10kV/EMAX-3770 (manufactured by HORIBA Corporation)), the processed sample was inspected by UTW mode of existence.

In addition, for each of the HAP powder samples treated with the compositions of Example 1 and Comparative Example 1, fluorine (19F) was detected by temperature programmed desorption (TPD) by mass spectrometry (instrument: TPD (manufactured by BEL JAPAN Corporation), 0.1 g sample, vacuum, program rate 10°C/min).

Further, each component of the HAP powder sample treated with the composition of Example 1 was identified and quantified by ion chromatography. The sample was prepared in such a manner that 0.1 g of HAP powder sample was accurately weighed in a beaker, 40 ml of ultrapure water was poured thereinto, and 0.5 ml of 0.01 mol/l hydrochloric acid was added, followed by stirring for 1 hour. The slurry was filtered through a membrane filter with a pore size of 0.45 μm. 5 ml of the initially filtered solution was discarded, and the subsequently filtered solution was used as the solution for ion chromatography measurements. This ion chromatogram was measured by DX320 (equipped with EG-40) (manufactured by Dionex Corporation), and in the measurement, monofluorophosphate and glycerophosphate were identified by comparing their retention times with a reference material, and by the standard curve method Quantitative determination from peak area.

The conditions for the quantitative analysis of monofluorophosphate and glycerophosphate are as follows, separation column: IonPac AS-16 (manufactured by Dionex Corporation); guard column: Ionpac AG-16 (manufactured by Dionex Corporation); elution solvent: KOH (using EG-40) ; flow rate: 1.0 ml/min; gradient: 10 mmol/l to 70 mmol/l (0 to 20 min.); suppressor: ASRS (200 mA); and detector: conductivity detector.

(3) Results

a. The amount and status of fluorine adsorption on HAP pellets

As shown in Table 1, the amount of fluorine adsorption on the HAP pellets treated alternately with the composition (X) and the composition (Y) in Example 1 is 33 mg/m ² , wherein the composition (X) contains calcium glycerophosphate and sodium monofluorophosphate, the composition (Y) contains sodium fluoride.

That is to say, in the case of Example 1, the calcium fluoride microparticles (primary particles) formed by sodium monofluorophosphate inhibit the formation of secondary particles due to the presence of calcium glycerophosphate, so the fluoride in the form of primary particles Calcium particles can be efficiently adsorbed on the HAP pellets, and thus the adsorption amount of fluorine on the HAP pellets is 33 mg/m ² .

Furthermore, in the case of Example 2 containing component (A) in which component (A) contained calcium glycerophosphate, calcium lactate and sodium monofluorophosphate, when alternately using composition (X) and composition (Y) The adsorption amount of fluorine on the treated HAP pellets was 28 mg/m ² .

Both Example 1 and Example 2 were confirmed by the observation of good adsorption status of calcium fluoride by SEM, and they were rated as "◯" (Table 1).

In contrast, in the case of Comparative Example 1 including the composition (X) containing calcium lactate, the adsorption amount of fluorine on the HAP pellets treated alternately with the composition (X) and the composition (Y) was 20 mg/m ² .

Here, although only 0.5 wt.% of calcium lactate was contained in the composition (X), the adsorption amount of fluorine on the HAP pellets in Example 2 was 28 mg/m ² , on the contrary, in Comparative Example 1 by The adsorption amount of fluorine on HAP pellets treated alternately with composition (X) and composition (Y) containing 1 wt.% calcium lactate was 20 mg/m ² , so its adsorption amount was lower than that in Example 2.

This is because the calcium fluoride particles (primary particles) formed by calcium lactate in the composition (X) and sodium fluoride in the composition (Y) contain 0.5 wt.% in the case of Example 2 The glycerophosphate inhibits the formation of secondary particles. Due to the effect of glycerophosphate inhibiting the formation of secondary particles, calcium fluoride particles as primary particles exist in large quantities, and such particles (primary particles) are effectively adsorbed on HAP spheres, thus obtaining a fluorine adsorption amount of up to 28mg/ ^m2 level.

In contrast, in Comparative Example 1, since the composition (X) contained only calcium lactate, the calcium fluoride microparticles ( Primary particles), and the subsequent aggregation is too fast and out of control to form large-sized secondary particles. The adsorption of such large-sized secondary particles on the HAP pellets was not sufficiently effective, and as a result, the adsorption amount of fluorine became 20 mg/m ² , which was a low value compared with Example 2.

In addition, in the case of alternate treatment of the composition (X) containing only calcium glycerophosphate and the composition (Y) containing sodium fluoride, such as the case of Comparative Example 2, the formation of calcium fluoride primary particles is slow (see Figure 1 ), as a result, the amount of fluorine adsorbed on the HAP pellets became 14 mg/m ² .

In Comparative Example 3, when the composition (X) containing only sodium monofluorophosphate and the composition (Y) containing sodium fluoride were alternately treated, no formation of calcium fluoride primary particles was observed.

The adsorption state of calcium fluoride observed by SEM is shown in Table 1. In Comparative Example 1 and Comparative Example 2, the state of partial adsorption of calcium fluoride could be confirmed, and rated as "Δ". In Comparative Example 3, the state that calcium fluoride was rarely adsorbed was confirmed, and was rated as "X.

b. Adsorption of calcium fluoride particles on HAP powder

FIG. 2 is an SEM photograph of adsorption of calcium fluoride particles on HAP powders treated with compositions (X) and (Y) in Example 1. FIG. In Fig. 2, it can be confirmed that small particles are adsorbed on the stick-shaped HAP powder. The particles are calcium fluoride particles, and they are mainly secondary particles.

FIG. 3 shows the state of adsorption of calcium fluoride microparticles on HAP powders treated by compositions (X) and (Y) in Comparative Example 1. FIG. In Fig. 3, secondary particles larger than in Example 1 (Fig. 2) can be demonstrated on the rod-shaped HAP powder.

The generation of large secondary particles is due to the absence of glycerophosphate, which cannot control or prevent the rapid progress of secondary aggregation.

The adsorption status of calcium fluoride particles on the HAP powder treated by comparing compositions (X) and (Y) in Example 3 is shown in FIG. 4 . As shown in FIG. 4 , in Comparative Example 3, calcium fluoride fine particles could hardly be confirmed on the HAP powder. Because, in the case of the treatment of the composition (X) containing only sodium monofluorophosphate (see Table 1) and the composition (Y) containing sodium fluoride, calcium fluoride particles were hardly formed.

c. Change in turbidity after mixing composition (X) and composition (Y)

The change in turbidity after mixing the two compositions (X) and (Y) is shown in Figure 1 . Here, the turbidity (adsorption at 600 nm) reflects the formation status of calcium fluoride fine particles (secondary particles). As shown in FIG. 1 , in the case of Example 1, the adsorption rapidly increased immediately after mixing the composition (X) and the composition (Y), and then gradually decreased. This means that after the rapid formation of calcium fluoride particles, the particle size is controlled.

In contrast, in comparing the turbidity after mixing the composition (X) and the composition (Y) in Example 1, the adsorption showed a tendency to increase with time within 10 seconds after mixing. This shows normal formation behavior of calcium fluoride particles. Also, in Comparative Example 2 (composition of JP-A-10-511956), improvement in adsorption was hardly confirmed for about 10 seconds after mixing composition (X) and composition (Y). This means that the formation of calcium fluoride particles is suppressed.

d. X-ray diffraction analysis of calcium fluoride primary particle (crystal particle) size

The presence of CaF ₂ can be confirmed by the diffraction peaks of CaF ₂ (PDF#35-0816) d=3.1546 (111), d=2.7314 (200) and d=1.9316 (220). Only the spectrum close to d=3.1546 is shown in FIG. 5 . Note that the range of CaF ₂ d = 3.1546 (111) is the easiest to separate and does not overlap with the peak of hydroxyapatite, between the diffraction peaks of HAP powder treated by different treatment methods and the diffraction peak of untreated HAP powder (control) The difference in intensity between them was measured in the range of 2θ 26.0 to 31.0 degrees, respectively. Then only the peak of _CaF2 was separated (S1 and S2 in Fig. 5). Using the diffraction angle and half-width (width at half the peak height) of this isolated peak (CaF ₂ ), the crystal size (A: Angstrom) is calculated by Scherrer's equation (D=Kλ/B·cosθ), where the coefficient K= 0.9, CuKαλ=1.54056 angstroms, B: the half-width of the peak (the width (rad) at half the height of the peak), and θ is the diffraction angle (the position of the peak top).

As a result, the size of the crystals in Example 1 was 4 nm, and the size of the crystals in Comparative Example 1 was 13 nm.

e. Component analysis of calcium fluoride secondary particles

In the HAP powder sample treated with the composition of Example 1, carbon was detected from the SEM-EDS measurement results, and it could be confirmed that it was derived from the carbon of glycerophosphate adsorbed on the HAP powder sample.

In the HAP powder sample treated with the composition of Example 1, the desorption peak of fluorine originates from the decomposition above approximately 400°C, which is measured at 19F from mass spectrometry by temperature programmed desorption (TPD). On the other hand, in the HAP powder sample treated with the composition in Comparative Example 1, the analytical peak derived from decomposed fluorine was not obtained near 400°C or higher. That is to say, it can be confirmed that calcium fluoride is stable and does not decompose through the HAP powder sample treated with the composition in Comparative Example 1, and it can be confirmed that the fluorine detected in the HAP powder sample treated with the composition of Example 1 It is derived from monofluorophosphate.

From the above analysis results, it can be confirmed that both glycerophosphate and monofluorophosphate are adsorbed on the HAP sample powder treated with the composition of Example 1, and the value determined quantitatively by ion chromatography is 1.0 wt.% monofluorophosphate and 2.9 wt.% glycerophosphate.

f. The effect of inhibiting demineralization

The results of the potentiometric titration are shown in FIG. 6 . If phosphate or calcium ions are lost from the tooth (ie, demineralized), the concentration of phosphate or calcium ions in the solution will increase and the change in pH will decrease when hydrochloric acid is added. If the loss of phosphate ions or calcium ions from teeth is inhibited, the concentration of phosphate ions or calcium ions in the solution will decrease and the pH of the solution will be greatly changed by adding hydrochloric acid. Based on this principle, the effect of mouthwashes on inhibiting demineralization was evaluated.

As shown in Figure 6, the untreated HAP powder dissolves at a pH lower than about 5.5, but the HAP powder in Example 1 dissolves at a pH lower than about 4.5, and the HAP powder in Comparative Example 1 dissolves at a lower pH at about 5.1. This means that the treatment with the composition in Example 1 is more effective in inhibiting demineralization than the treatment with the composition in Comparative Example 1.

2. Dentifrice

(1) Preparation of dentifrice

Two compositions, namely the composition containing calcium glycerophosphate and sodium monofluorophosphate (X ₁ ) and the composition containing sodium fluoride (Y ₁ ) were prepared according to the compositions shown in Tables 2 and 3, respectively. Each of the prepared compositions is then placed into each compartment of the dentifrice container, which consists of a tube divided inside by a partition, allowing each component to be dispensed in equal amounts into separate compartments. within the partition.

Table 2

Composition (X ₁ ) (wt.%) sodium monofluorophosphate 0.72 calcium glycerophosphate 1 Sorbitol solution (70wt.% solution) 40 Calcium carbonate ^* 2 15 polyethylene glycol 600 4 citric acid 0.1 Sodium sucrose 0.1 Sodium dodecyl sulfate 1.2 Silicic anhydride 7 Sodium carboxymethyl cellulose 1 flavoring agent 1 pure water balance total 100

^* 2: The average particle size is 150 microns

table 3

Composition (Y ₁ ) (wt.%) sodium fluoride 0.21 Xylitol 9 Sorbitol solution (70wt.% solution) 32 polyethylene glycol 600 4 Sodium sucrose 0.1 Sodium dodecyl sulfate 1.2

Silicic anhydride 20 Sodium carboxymethyl cellulose 1.5 flavoring agent 1 pure water balance total 100

Two compositions, the composition containing calcium glycerophosphate and sodium monofluorophosphate (X ₂ ) and the composition containing sodium fluoride (Y ₂ ) were prepared according to the compositions shown in Tables 4 and 5, respectively. Each prepared composition is then placed into each compartment of the dentifrice container, which consists of a tube whose interior is divided by a partition so that each component is dispensed in equal amounts into separate compartments. within the partition.

Table 4

Composition (X ₂ ) (wt.%) sodium monofluorophosphate 0.72 calcium glycerophosphate 0.7 Sorbitol solution (70wt.% solution) 35 calcium lactate 0.5 lactic acid 0.3 Polyethylene glycol 600 4 Xylitol 6 Sodium sucrose 0.1 Sodium dodecyl sulfate 1.2 Silicic anhydride 17 Sodium carboxymethyl cellulose 0.9 carrageenan 0.2 xanthan gum 0.2 flavoring agent 1 pure water balance total 100

table 5

Composition (Y ₂ ) (wt.%) sodium fluoride 0.21 Xylitol 6 Sorbitol solution (70wt.% solution) 35 Polyethylene glycol 600 4 Sodium sucrose 0.1 Sodium dodecyl sulfate 1.2 Silicic anhydride 17 Sodium carboxymethyl cellulose 0.9 carrageenan 0.2 xanthan gum 0.2 flavoring agent 1 pure water balance total 100

(2) Evaluation of oral preparation system

<1>Effect of remineralization

A. Materials and methods

1) Preparation of demineralized teeth

Extracted human molars were used as dental samples. The enamel portion of this tooth sample with a cavity of size 3 mm x 3 mm was soaked in 0.1 M lactate buffer (pH: 4.5) at 37° C. for three days to form an artificial subsurface demineralization lesion.

2) Remineralization treatment of teeth in the human oral cavity

The demineralized teeth were fixed in the oral cavity of 10 healthy adult subjects aged 30 to 40 years old through resin stents and fitted with an oral mandibular arch.

(i) Dentifrices for tooth remineralization treatment

Dentifrices for tooth remineralization treatment are as follows: In Example 3, as a two-part dentifrice, a dentifrice containing a composition (X ₁ ) of calcium glycerophosphate and sodium monofluorophosphate and containing fluoride The sodium composition (Y ₁ ) is placed in a combined container, the inside of which is divided into two partitions by a partition, so that each component is distributed to each partition in a 1:1 ratio; The dentifrice in comparative example 5, wherein only the composition (X ₁ ) in Table 2 is put into a container with a single partition; the dentifrice in comparative example 4, wherein the composition in Table 3 (Y ₁ ) into another container with a single compartment.

(ii) Use of dentifrice

The dentifrices in Example 3, Comparative Example 4, and Comparative Example 5 were used by the subjects, respectively.

As shown in FIG. 7, the holder was attached to the oral cavity of the examinee for 24 hours, and the dentifrice was used by the examinee three times a day in the usual manner. Thereafter, the rack is removed from the mouth, and the sample fragments are isolated. In the same subject, a group of 24 days was repeated three times according to the method described above.

3) Determination of tooth remineralization by contact microradiography (Contact Microradiography (CMR))

After remineralization treatment, each sample section was dissected and polished to a thickness of approximately 150 microns and photographed by CMR. The resulting CMR image (soft X-ray image) is analyzed by image analysis to measure the amount of mineral loss (ΔZ). Here, it should be noted that ΔZ is the product of the concentration of the demineralized fraction and the depth of demineralization from the surface (vol%·µm).

In addition, this group used the mineral recovery rate (%) of each dentifrice to calculate by the following formula:

{(△Z(baseline) before remineralization treatment-△Z after remineralization treatment)/△Z(baseline) before remineralization treatment}×100

A higher value of mineral recovery rate means a higher level of remineralization.

B. Results

Figure 8(a) shows a photograph of an X-ray micrograph of a cross-section of a tooth. In FIG. 8(a), a gray portion can be recognized between the surface of the tooth and the depth of the enamel. The light gray part means a better situation of mineral recovery in the tooth. In FIG. 8( a ), it can be confirmed that the tone of the gray portion in Example 3 is the lightest among the three. This shows that the remineralization effect in Example 3 is higher than that in Comparative Example 4 and Comparative Example 5.

As shown in FIG. 8( b ), in all groups using the dentifrices of Comparative Example 4, Comparative Example 5, and Example 3, it could be confirmed that ΔZ was greatly reduced relative to demineralized teeth (remineralization proceeding). In the group using the dentifrice of Comparative Example 4, the mineral recovery rate (%) calculated from ΔZ was 22%, in the group using the dentifrice of Comparative Example 5 was 12%, and in the group using the dentifrice of Comparative Example 3 The dentifrice group was 41%. This can prove that the oral preparation system of the present invention, for the group using the dentifrice of Example 3, obtained the highest effect of promoting remineralization.

<2> Effect of suppressing pH drop due to residual plaque

A. Materials and methods

A dentifrice for evaluating the effect of suppressing the pH drop was prepared as follows. As in the dentifrice in Example 4, a two-dose dentifrice combining a calcium glycerophosphate-containing composition (X ₂ ) and a sodium fluoride-containing composition (Y ₂ ), in which sodium monofluorophosphate is further Included in composition (X ₂ ). As in the dentifrice of Comparative Example 6, only the composition (Y ₂ ) containing only sodium fluoride was used.

About 1 g of the dentifrice of Example 4 was used for 1 minute by a subject who had been interrupted from oral cleaning for 2 days. Plaque was collected immediately afterwards. 30 mg of collected plaque was added to 1 ml of suspended 5% sucrose solution and kept at 37°C for 10 minutes. Afterwards, changes in pH were repeatedly measured at 10-minute intervals. The dentifrice in Comparative Example 6 was used by the examinee in the same manner as before, and the change in pH was measured with the plaque collected according to the above method.

B. Results

When using the dentifrice of Example 4, the pH of the plaque changed from pH6.8 to pH6.4 after 10 minutes, and the pH of the plaque after using the dentifrice of Comparative Example 6 changed from pH6 to pH6 after 10 minutes. .8 to pH 5.4. That is, it could be confirmed that the change in pH of residual plaque after using the dentifrice of Example 4 was smaller than that of Comparative Example 6, and that the decrease in pH of residual plaque was suppressed by using the dentifrice of Example 4. It can be speculated that because the glycerophosphate with pH buffering ability derived from the dentifrice of Example 4 is mixed into the secondary particles of calcium fluoride when forming calcium fluoride, the effect of inhibiting the pH reduction of residual plaque is obtained .

Claims (12)

1. A multi-composition oral preparation system is characterized in that comprising the following components: (A) a calcium ion-donating compound, (B) compounds donating fluoride ions but not monofluorophosphate ions, (C) compounds providing polyhydroxyphosphate ions and (D) a compound providing a monofluorophosphate ion, Wherein components (A) and (B) are separated in the oral preparation system. 2. The oral preparation system according to claim 1, characterized in that components (A), (B), (C) and (D) are mixed in the oral cavity, or mixed immediately before being introduced into the oral cavity. 3. The oral formulation system according to claim 2, characterized in that calcium fluoride particles are formed when all components are mixed. 4. The oral preparation system according to claim 1, characterized in that the system has any one of the following combinations: A system comprising a composition comprising components (A), (C) and (D), and a separate composition comprising component (B); A system comprising a composition comprising component (A), and a separate composition comprising components (C), (D) and (B); A system comprising a composition comprising component (A) and component (C), and a separate composition comprising component (B) and (D); A system comprising a composition comprising components (A) and (D), and a separate composition comprising components (B) and (C); A system comprising a composition comprising components (A) and (D), a separate composition comprising component (B), and another separate composition comprising component (C); A system comprising a composition comprising components (A) and (C), a separate composition comprising component (B), and another separate composition comprising component (D); A system comprising a composition comprising components (B) and (D), a separate composition comprising component (A), and another separate composition comprising component (C); a system comprising a composition comprising components (B) and (C), a separate composition comprising component (A), and another separate composition comprising component (D); and A system comprising a composition comprising component (A), a separate composition comprising component (B), a separate composition comprising component (C), and a separate composition comprising component (D). 5. The oral preparation system according to claim 3, characterized in that the primary particle size of the calcium fluoride particles is 0.3 to 15 nm. 6. The oral dosage system of claim 3, wherein secondary particles are formed from aggregates of calcium fluoride particles, wherein the secondary particles comprise monofluorophosphate and/or polyhydroxyphosphate. 7. The oral preparation system according to claim 6, characterized in that the content range of the monofluorophosphate is 0.05 to 20wt.% of the secondary particle, and the content range of the polyhydroxyphosphate is the secondary particle 0.05 to 20 wt.% of the particles. 8. The oral preparation system according to claim 1, characterized in that component (A) and component (B) are in different spaces before mixing. 9. The oral preparation system according to claim 1, characterized in that the compound providing calcium ions is at least one polyhydroxy group selected from calcium glycerophosphate, glucose-1-calcium phosphate and glucose-6-calcium phosphate calcium phosphate. 10. The oral preparation system according to claim 1, characterized in that the compound providing polyhydroxyphosphate ions is at least one selected from calcium glycerophosphate, glucose-1-calcium phosphate and glucose-6-calcium phosphate polyhydroxycalcium phosphate. 11. A multi-component oral preparation system, characterized in that it comprises the following components: (B) compounds donating fluoride ions but not monofluorophosphate ions, (D) a compound providing a monofluorophosphate ion, (E) Polyhydroxycalcium Phosphate Wherein components (B) and (E) are separated in the oral preparation system. 12. An oral preparation containing a multi-composition system comprising composition (X) and composition (Y), characterized in that component (C) is mixed in the multi-composition system: (X) a first composition comprising (A) and (D); (Y) a second composition comprising (B); (A) compounds providing calcium ions; (B) compounds that donate fluoride ions; (C) a compound that provides polyhydroxyphosphate ions; and (D) Compounds that donate monofluorophosphate ions.

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