CA2017918A1 - Fluoride colloid and oral composition - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Disclosed is a colloidal solution comprising colloidal particles of a scarcely water-soluble fluoride having a particle size of 0.005 to 1 micron in a fluoride ion concentration of 1 to 10,000 ppm. The colloidal solution is particularly useful, among others, for preventing tooth decay.

Description

Z~1791~

Fluoride Colloid and ~ral Composition The present invention relates to a colloidal fluoride solution and a process for producing lt.
In particular, the present invention provides a colloidal solution of a hardly soluble fluoride which gives a fluoride ion concentration of 1 to 10,000 ppm when dissolved in water. The colloid of the present invention can be used alone or in the form of an oral compo!;itioncontaining it in such an amount that the fluorine content thereof is 10 to 100,000 ppm and other substances for preventing tooth decay.

Zi-1179~8 The present invention also relates to an oral composition characterized in that fluorine and calcium contained therein are at least partially reacted with each other to form a colloidal fluoride in the presence of a suitable saccharide derivative as a peptizer to enhance th availability of fluorine for the tooth and improve its effect of preventing the tooth from decaying.

[Prior Art]
Various compounds were proposed as components effective in preventing tooth decay.
Among them, those which are deemed to be the most effective are fluorides such as sodium fluoride, sodium monofluorophosphate and stannous fluoride.
The fluorides are effective mainly due to the fluoride ions for improving the acid resistance of the tooth and accelerating recalcification of a decayed tooth in its early stage wherein the decalcification has proceeded only slightly. The effect of improving the acid resistance of the tooth is thought to be due to the fact that the fluoride ions are incorporated into a crystal lattice of hydroxyapatite which is the main constituent of the tooth enamel or, in other words, fluoride ions partially fluorinate hydroxyapatite 2~117~318 and simultaneously repair the lattice irregularities.
The recalcification is a reaction for recovering or substantially recovering the hydroxyapatite, which was shortened, modified or lost by the decalcification of the enamel, by a reaction reverse to the decalcification to inhibit the decaying of the tooth.
This reaction ordinarily proceeds in addition to the decalcification and is remarkably accelerated in the presence of a fl~oride ion.
These effects are quite peculiar to the fluoride ion and there is no substitute for this ion. Fluorides are thus added to tap water, used in the form of tablets to be crushed with the teeth, added to foods, applied to the tooth surface or added to mouth-washes or dentifrices.
As for the extent of the effect of the fluorides for preventing the tooth from decaying, it is 50 to 65% when it is added to tap water, 30 to 40% when it is applied to the tooth surface, and 20 to 50%
when it is used in the form of a mouth-wash or dentifrice. Although the effect of the iodides is far more remarkable than that of other agents for preventing tooth decay, complete prevention of the decay is still ideal. From this point of view, the effect of the fluorides is yet insufficient.

Z~-J179:~8 In particular, when the fluoride is not orally administered but directly applied to the tooth (local application) as in the case of a mouth wash or dentifrice, the effect thereof for preventlng the decaying of the tooth is yet small. Thus it leaves much room for improvement.
Under these circumstances, investigations are being made for the purpose of finding a new composition for improving the effect of the fluoride, a new method of treating the tooth or a new fluorine compound.
Particularly in the local application, the efficiency of fluorine uptake is low and a large amount of fluorine is d.isgorged without exhibiting any effect, so that various investigations are in progress for increasing the fluorine uptake.
In successful inve'stigations, sodium fluoride acidified with phosphoric acid is used. In this case, phosphoric acid is used for increasing the fluorine uptake. This agent has been already widely used.
Recently, investiqations are made for the purpose of incorporating 1,500 to 2,000 ppm (1.5 to 2 times as high as the ordinary concentration) of fluorine into a dentifrice in order to increase the fluorine uptake. Supposedly this method is effective.

Z~ 7918 The mechanism of exhibiting such a remarkable effect can be explained as follows: since the fluoride is locally applied for only a very short time, only a very small amount of the fluoride is used for the direct fluorination of the tooth and the reset acts to disintegrate part of the tooth to form calcium fluoride, which is dissolved in saliva to release fluoride ions which fluorinate the tooth. When sodium fluoride acidified with phosphoric acid or a fluoride of a high concentration is used for the treatment, the very calcium fluoride is formed in a large amount to indirectly increase the effect of reinforcement of the tooth.
However, on the other hand, the tooth must be partially disintegrated in the treatment with the acidic sodium fluoride or the fluoride of a high concentration, so that some problems might occur during the application for a long period of time.
Further, the acute toxicity of fluofine is by no means low, and the increase of the fluorine concentration is undesirable when it is taken by mistake.
Another expected method of accelerating the fluorine uptake comprises using various metallic ions in combination with the fluoride. For example, 2~7918 aluminum ion and calcium ion [J. Kyushu Dental Soc., 4 (1): 247 to 259] and lanthanum CJap. J. Pedodontics, 25 (1): 1 to 11~ have the effect of accelerating the fluorine uptake.
The mechanism is as follows: the insoluble fluoride thus formed is adsorbed on apatite. When the metallic ion is a calcium ion, the insoluble fluoride is the very calcium fluoride. In principle, this is similar to the treatment with the fluoride of a high concentration. However, the enamel is not disintegrated unlike the treatment with the fluoride of a high concentration.
Another subsidiary effect, in addition to the effect of acceleration of the fluorine uptake, of the metallic ions incorporated there1nto has also been known.
For example, it is known that a calcium ion has an effect of accelerating the recalcification and that a combination thereof with the fluorine-containing agent is effective. Examples of the combinations are disclosed in Japanese Patent Laid-Open Nos.
039642/1972 (Beecham Group) and 091339/1975 (Procter & Gamble) and some of them are available on the market.
It is known that titanium, etc. have an effect of improving acid resistance owing to their coating Zl-J 17918 effect.
Therefore, a composition comprising a combination of a fluoride ion with a metallic ion is expected to be quite useful.

However, the composltion comprising the combination of a fluo:ride ion with a metallic ion ha~ many problems to be solved when it is practically used.
Fluorides of calcium, magnesium, strontium, lanthanoids such as lanthanum, molybdenum, manganese, aluminum and indium having the effect of preventing the tooth from decaying are insolbule or hardly soluble in water~ When an aqueous solution of such a fluoride is left to stand for a while, it precipitates and almost loses its reactivity. Hence it is impossible to realize a high fluorine uptake or to exhiblt the ordinary effect of fluorides.
Under these circumstances, investigations are in progress on the formulation of compositions capable of keeping the remarkable effect of the fluoride.
The processes heretofore proposed include, for example, a process di.sclosed in Japanese Patent Laid-Open No. 212112~1982 (Colgate-Palmolive) wherein aluminum and fluorine are kept in an oil layer and 2~17918 an aqueous layer, respectively, so that they are mixed at the time of use, a process disclosed in Japanese Patent Laid-Open No. 219107/1~83 (Procter & Gamble) wherein most of calcium ions are protected by chelation and a process disclosed in Japanese Patent Laid-Open No. 091339/1975 (Procter & Gamble) wherein the pH of the solution ls extremely lowered.
However, these processes have defects. Namely, the emulsion has a special texture which is unsuitable for giving pleasantness in its use. The chelation of calcium sacrifices the effect of the dentifrice.
The low pH restricts the formulation and is not good for the tooth.
It is well known that fluorine has an effect of preventing tooth decay. Fluorine is added in a very small amount labout 1 ppm) to tap water, incorporated into a dentifrice or mouth-wash (1,000 ppm or less) or applied to the surface of the 9 2lll7~8 tooth (about 10,000 ppm) by dentists. The effect of preventing the tooth from decaying is most remarkable when it is added to tap water and the effect is halved when it is incorporated into the dentifrice or mouth-wash. However, the incorporation thereof into the dentifrice or mouth-wash is desirable, since it is easy and economically advantageous.
Thus one of the problems in the field of dental hygiene is an improvement of the above-described effect.
The essential action mechanism of the prevention of the tooth from decaying with the use of fluorine is that hydroxyapatite (hereinafter referred to as HAP), a constituent of the enamel of the tooth, is converted into fluoroapatite (hereinafter referred to as FAP) to improve the acid resistance of the tooth. The reaction of forming FAP from HAP slowly proceeds in the presence of fluoride ions of a low Z~Ç17918 concentration. The addition of fluorine to tap water is quite effective, since fluorine taken into the body by drinking the tap water is continuously secreted into saliva in a very small amount over a long period of time to exhibit its effect on the tooth and cause the conversion of HAP to FAP. When fluorine is incorporated into a dentifrice, no conversion of HAP into FAP can be expected in a short time of brushing the teeth. However, it was found that when fluoride ions of a high concentration acted on the enamel of the tooth, HAP was partially decomposed at a relatively high reaction rate to form calcium fluoride on the surface of the tooth, and calcium fluoride thus formed after the brushing of the tooth was slowly dissolved to release fluoride ions to thereby cause the conversion of HAP into FAP.
Therefore, the larger the amount of fluorine incorporated into the dentifrice, the larger the calcium fluoride deposited on the surface of the tooth and the more remarkable the effect. However, the upper limit of the fluorine content is regulated to be 1,000 ppm at present in due consideration of a risk of drinking it by mistake.

As described above, the fluoride ion contained 65702_365 2~ ~ 7-~ ~8 in a dentifrice or mouth-wash forms calcium fluoride by the chemi-cal reaction on the surface of the tooth, thereby deposited there-on, and then exhibits the effect of preventing the tooth from decaying after the conversion of HAP to FAP. Therefore, it is necessary to bring the fluoride ion of an as high as possible con-centration into contact with the tooth for an as long as possible time when the tooth is brushed with the dentifrice. Since, how-ever, the upper limit of the fluorine content in the dentifrice is regulated and the time of brushing the tooth cannot be prolonged so much, there remains a problem that the uptake of fluorine by the tooth cannot be sufficiently increased.
Summary of the Invention After investigations, the inventors have succeeded in forming a colloidal solution of fluoride precipitate that is hard-ly soluble in water. On the basis of this finding, the inventors have succeeded in developing a composition comprising the colloid that increases the fluorine uptake by the tooth enamel. The fluorine thus taken up is then gradually released over a long period of time, exhibiting a tooth decay preventing effect far superior to that of ordinary fluorine-containing compositions.

Z~'1791~3 The composition also has an excellent storage stability and tooth decay can be effectively prevented with an oral composition containing this colloidal solution.
After intensive investigations made for the purpose of finding a new fluorine-containing agent having an excellent effect of supplying fluorine to the tooth, the inventors found that especially a colloidal dispersion of calcium fluoride formed by reacting fluoride ions with calcium ions exhibited a quite high adhesion to the tooth and a quite excellent effect of supplying fluorine to the tooth immediately after the reaction. However, it was also found that thiq effect decreased as the colloidal calcium fluoride present in the dispersion aggregated to form a precipitate with the lapse of time.
After further intensive investigations made for the pur-pose of retaining the effect of the colloidal calcium fluoride for a long period of time, the inventors have found that when fluoride ions are reacted with calcium ions in the presence of a peptizer comprising a particular saccharide derivative, a colloidal fluor-ide having an extremely small particle diameter can be formed and it exhibits an extremely high adsorption to the tooth. Therefore, 2i)17918 it can efficiently supply fluorine to the tooth to improve its resistance to decaying. Further, the colloid has a high stability and its effect lasts for a long period of time. The present invention has been completed by applying it in the production of an oral composition.
Thu~, one aspect of thé present invention provides a colloidal solution comprising colloidal particles of a fluoride that is hardly soluble in water. The particles have a particle size of 0.005 to 1 micron. The fluoride has such a low solubility in water that the fluoride ion concentration is 1 to 10,000 ppm in the saturated solution.
The solution may further comprise a peptizer (namely, stabilizer) facilitating the colloidization of the fluoride.
The solution may contain 1 to 100,000 ppm, based on the entire qolution, of fluorine in the colloidal particle~ while 10 to 100 percent by weight of the fluorine contained in the entire solution is included in the colloidal particles.
The peptizer is preferably selected from polyol phosphoric acids, polyol sulfuric acids, polyol carboxylic acids io and salts of these acids.

2~:J17918 Preferably the solution contains 1 to 95,000 ppm, based on the entire solution, of fluorine in the colloidal particles whereas 10 to 95 percent by weight of the fluorine contained in the entire solution is included in the colloidal particles. The rest of the fluorine is present in the dissolved for~ in water.
The invention also provides processes for preparing the colloidal solution of the fluoride hardly soluble in water.
One of such processes comprises mixing a water-soluble fluoride with a water-soluble cation salt to form precipitates of the hardly-water-soluble fluoride and then adding a peptizer to the precipitates to produce colloidal particles having a particle size of 0.005 to 1 micron in water.
Alternatively, the colloidal solution of the fluoride hardly soluble in water, may be prepared by mixing an aqueous solution of a water-soluble fluoride with an aqueous solution of a water-soluble cation salt to form precipitates of the water-hardly-soluble fluoride, wherein at least one of the two solutions con-tains a peptizer, to produce colloidal particles having a particle size of 0.005 to 1 micron in water.
The colloidal solution may also be prepared by some 2nl7sls other methods which are described hereinafter.
Where desired, colloidal particles of the water-hardly-soluble fluoride can be obtained by removing water from the colloidal solution produced by the process as mentioned above.
It is preferable that the water-soluble fluoride i8 a water-soluble hydrofluoric acid and the water-soluble cation salt i9 a water-soluble calcium salt.
The invention further provides an oral composition com-prising a water-soluble fluoride, a water-soluble cation salt and a peptizer.
The composition preferably contains 10 ppm or more of fluorine, more preferably from 10 ppm to 100,000 ppm of fluorine, mo~t preferably from 150 ppm to 60,000 ppm of fluorine.
It is preferable that the composition contains 0.01 to 100 mol parts of the fluoride and 0.01 to 100 mol parts of a saccharide (as the peptizer), each per 1 mol part of calcium, more preferably 0.1 to 10 mol parts of the fluoride and 0.1 to 10 mol parts of the saccharide, each per 1 mol part of calcium.
The peptizer is preferably a polyol phosphate, a polyol sulfate, a polyol carboxylate or a salt of one of these.
In experiments, it was observed that up to 100 percent 2~791~

by weight of fluorine based on the total amount of fluorine contained in the colloidal solution could be present in the colloidal particles. This means that substantially all of the fluorine is present in the colloidal particles and substantially no fluoride is present in its dissociated ion form tF-). A
fluorine concentration may range from 10 to 100,000 ppm based the entire colloidal solution. The fluoride should be insoluble or scarcely soluble in water and should have such a low solubility that it gives a fluorine ion concentration of 1 to 10,000 ppm in the state of saturation.
In the invention, the formation of colloid in the solu-tion can be experimentally recognized by the following methods (1) to (4).
(1) The solution containing the three components, that is, the fluoride, the cation salt and the peptizer, is found to have a less amount of precipitates or a less turbidity than a control solution containing no peptizer, but the other two.
(2) The solution is filtered with a microporous filter having a pore size of 0.8 micron and 8 to 9 ml of the filtrate is collected in a bottle and is centrifuged with a ultra-centrifuging Z~ 7918 apparatus, such as SCP70H (trade-mark of Hitachi) SRP70AT, 50,000 rpm, 20 hours, 15 degree C. Precipitates shows formation of colloid.
(3) The solution is filtered with a microporous filter and the filtrate is found to have particle~ of 0.005 to 1 micron in view of dynamic light scattering, for example with the use of DLS-700 ~trade-mark of Otsuka Denshi Co., Ltd).
(4) The solution is found to have particles of 0.005 to 1 micron by determination with a transmis~ion electron microscope, HitachiR-7000. A test sample i8 prepared by filtering the sample with a microporous filter, placing the filtrated sample on a carbon support membrane having 200 A mesh, hydrophilically treated by JFC-llOO of Nippon Den~hi, 500 V, 2 mA, 20s x 3, remov-ing water and negative-dyeing with uranyl acetate.
The colloidal fluoride solution can also be prepared by dissolving the hardly soluble fluoride in water, in the form of fine colloidal particles having a diameter of 0.01 to 1 ~m in - water.
The colloidal solution of the present invention contains a compound which naturally precipitates if kept in a meta~table 2~17918 state. When the solution is subjected to a mechanical shock such as application to mouth, the metastable state is lost and the colloidal particles begin to precipitate and the precipitates thus formed deposit on the tooth. Since fluorine is contained in the colloidal particles, the deposit gradually releases fluorine. The higher the fluorine content of the particles, the better. From our experience, a fluorine content of at least 10 wt. ~ is effective.
Although the limit of the content of fluroine in the particles has not yet been elucidated, the highest content thereof recognized in the experi~ents was 95%.
According to experiments, the fluorine concentration based on the entire colloidal solution can be 10 to 1,000,000 ppm.
Although the reasons for them have not yet been eluci-dated, supposedly they are related to the mechanism of the forma-tion of the colloid.
Such a colloid i8 obtained by suitably selecting the hardly or scarcely soluble fluoride capable of giving a fluoride ion concentration of 1 to 10,000 ppm when dissolved in water.
The hardly soluble fluoride is desirably calcium fluo-znl7sls ride, aluminum fluoride, magnesium fluoride, barium fluoride, titanium fluoride, strontium fluoride, indium fluoride or a lanthanoid fluoride such as lanthanum fluoride, or a compound containing ~uch a component in its structure.
The peptizer (or stabilizer~ is particularly effective in maintaining the stability of the colloid and adhesion thereof to, for example, the tooth.
The peptizer is desirably a compound having a structure of a polyolphosphoric acld such as glucose-l-phosphate and glucose-6-phosphate, a polyolsulfuric acid such as sucrose ~ulfate or a polyolcarboxylic acid such as gluconic acid, or salt~
of these acids.
It has been found that the solubility of the fluoride in the solution is quite high. Particularly when a sugar phosphate is used, the solubility is `-2 ~ Zi~l7918 high and a transparent colloidal solution containing up to 100,000 ppm (in terms of fluorine) of the fluoride can be obtained.
The amount of fluorine in the colloidal particles was 95,000 ppm (95% based on the whole colloidal solution).
Although it was expected that a higher concentra-tion of the colloidal solution might bring about a higher effect, the solubility of sodium fluoride was at most 20,000 ppm in terms of fluorine, so that the above-mentioned colloidal solution is superior to the conventional one in this respect.
The colloidal solution of the fluoride intended in the present invention is produced desirably by the following processes:
i) a process which comprises mixing a soluble fluoride such as sodium fluoride with a soluble cation salt such as calcium chloride in such amounts and ratio that a fluoride will be precipitated when water is added thereto, adding a suitable amount of water to the mixture, further adding a peptizer as soon as a precipitate is formed, and either agitating the mixture or treating it with an ultrasonic cleaning apparatus, ii) a process which comprises preparing both of an 2 ~ znl7sls aqueous solution of a solu~le fluoride such as sodium f:Luoride and an aqueous solution of a soluble cation salt such as aluminum chloride, dissolving a peptizer in at least one of these aqueous solutions, mixing both solutions together and either agitating the mixture or treating it with an ultrasonic cleaning apparatus, iii) a process which comprises mixing a soluble fluoride with the peptizer such as a salt of glycerophosphoric acid, e.g., calcium salt thereoL, adding water to the mixture, and either agitating the mixture or treating it with an ultrasonic cleaning apparatus, and v) a process which comprises isolating the formed colloid in solid form by ultra-centrifugation, drying at a reduced pressure or addition of an alcohol and dissolv~r~ the.dry colloid thus obtained again in water to give a sol-form colloidal solution.
The colloidal solutions of the hardly soluble fluoride produced by each of the above-described processes have the same physical and chemical properties and they are not different form one another depending on the processes. Namely, no difference can be found in the properties such as viscosity, electric conductivity, light scattering and results 2 ~ Z. .1~918 of elementary analysis.
Since the above-described processes are nothing but the examples of the production processes, any process wherein an insoluble or scarcely soluble fluoride is formed and simultaneously or thereafter a peptizer is added thereto to form the colloidal solution may be employed in the present invention.
Although the temperature in the process ranges preferably from room temperature to around 40C, other temperature conditions are also possible.
The fluorides to be used in the present invention are not particularly limited except for the solubility thereof.
The reason why a hardly soluble fluoride capable of forming a saturated solution thereof having a fluorine concentration of 1 to 10,000 ppm, preferably 1 to 4,000 ppm, is necessary is that when it is soluble, no precipitate is formed and the colloidization by the peptization is impossible, and that it is indispensable when the fluoride is used in the form of an oral composition for reinforcing the tooth that it is soluble to some extent to release fluoride ions at a suitable rate.
The soluble fluorides used for the purpose of forming the difficultly soluble fluoride in the present 2 3 Z~1179~8 invention are not particularly limited as far as they are capable of releasing fluoride ions. However, soidum fluoride or potassium fluoride which forms a palatable colloidal solution is most suitable for forming the oral composition.
The cations used for the purpose of forming the difficultly soluble fluoride in the present invention are not particularly limited.

The present invention relates to an oral composition comprising three ingredients, i.e. a water-soluble hydrofluoric acid (a first ingredient), a water-soluble calcium salt (a second ingredient) and a peptizer (a third ingredient) which accelerates the colloidization of a reaction product between the first ingredient and the second ingredient.
The fluorine sources usable for producing tlle 2 d~ Zi~179~8 colloidal fluoride of the present invention include hydrofluoric acid and pharmacologically acceptable water-soluble hydrofluorides such as sodium fluoride, potassium fluoride, lithium fluoride, ammonium fluoride and tin fluoride. The calcium sources usable herein include water-soluble calcium salts such as chloride, nitrate, acetate, glycerophosphate, glucose l-phosphate and glucose 6-phosphate.
The particular peptizers usable herein include one or more saccharide derivatives selected from the group consisting of saccharide phosphates such as glyceraldehyde 3-phosphate, ~-glycerophosphoric acid, ~-glycerophosphoric acid, erythrose 4-phosphate, ribose 5-phosphate, glucose l-phosphate, glucose 6-diphosphate, inositol monophosphate, inositol hexaphosphate, fructose l-phosphate, fructose 6-phosphate, fructose 1,6-diphosphate, ascorbic acid 2-phosphate and heptulose 7-phosphate; saccharide sulfates such as sucrose sulfate and ascorbic acid 2-sulfate; glyceric acid and gluconic acid; and salts of them.
When a calcium salt of the saccharide derivative has a high solubility in water, it can serve as both the second ingredient (water-soluble calcium salt) and the third ingredient (peptizer).

2 ~ Z~17gl~

When these ingredients are mixed together to give a solution and reacted at room temperature, an extremely fine, stable fluoride colloid can be prepared. The molar proportions of the fluoride ion, the calcium ion and the peptizer are as wide as 0.01 to 1 00/1/0.01 to 100. The molar ratio of fluorine to calcium is desirably as close as the ratio of the stoichiometrical amounts of them for forming a salt, namely, a ratio of the fluoride ion to the calcium ion of 2/1. The amount of the saccharide derivative is desirably sufficient for stabilizing the colloidal particles. Namely, the ratio of the calcium ion to the peptizer is as close to 1/1 as possible. In due consideration of these requirements, the proportions of the fluoride ion, the calcium ion and the peptizer are particularly preferably 0.1 to 10/1/0.05 to 20. When the ratio of the fluoride ion to the calcium ion in the combination of them is different from the stoichiometrical ratio of them for forming a salt, free fluoride ions or calcium ions which do not form colloidal particles are contained in the composition as a matter of course, but such ions do not impair the effect of the present invention.
The above-described colloidal fluoride particles are usually quite fine and the particle diameter is 21-~ 17918 often as small as about 10 nm. A homogenous colloidal fluoride in the form of a transparent solution can be prepared when the ingredients are used at ~uitable proportions under suitable condi-tions. Therefore, when the present invention i~ applied to the production of a transparent mouth-wash or dentifrice, the commer-cial value thereof can be further increased.
Fluoride ions in the oral composition of the present invention react with calcium ions and a suitable peptizer to form a fluoride colloid having an excellent effect of supplying fluo-rine to the tooth, whereby the composition has an excellent effect of preventing the tooth from decaying.
The oral compo~ition may take a variety of forms. One form i8 a liquid mouth-wash e~sentially composed of the colloidal solution. Another form i~ a tablet for making a liquid mouth-wash by dissolving in water. In thiA case, the colloidal particles in gel or powder form prepared by removing water from the colloidal solution are suitable. When tooth paste is to be formulated the colloidal particle~ are also suited. The method and other ingredients for formulating these oral compositions are well-known in the art.
Brief Descrition of Drawing Fig. 1 is a graph showing the effect of the invention.
Fig. 2, 3 and 4 show data for obtaining fluorine amounts.
Example The solution will be explained in reference to its examples.

Z3~:~7918 2'( In determination of a fluorine ion concentration, one example is shown below.
4.87 g of potassiuim glucose-l-phosphate tetrahydrate, 1.1 g of sodium fluoride and 1.44 g of calcium chloride are added to 100 ml of water. The solution is allowed to stand for 1 day. With the use of F-NMR, JNM GX-270 of Nippon Denshi, a ratio of fluorine in the colloid to fluorine ion in the solution is determined from integral products of their peaks. It is resulted that a ratio of the fluoride in the colloid to the fluorine ion in the solution is found to be 100:0. See Fig. 2. All the used fluoride is distributed to the formed colloids.
Fig. 3 shows peaks of fluorine in the colloid and fluorine ion in the solution, respectively, obtained by adding 4.87 g of calcium glucose-l-phosphate tetrahydrate and 1.1 g of sodium fluoride to 100 ml of water and allowing it to stand for 1 day, determined by the above shown NMR. Fig. 4 shows determination of colloidal particles having a size of about 5 nm, obtained by adding calcium glucose-l-phosphate tetrahydrate and sodium fluoride at a mole ratio of 1:2 to water to reach the entire fluorine concentration of 500 ppm and allowing it to stand for 1 day, using the dynamic light scattering method.

2~ 7918 Now the description will be made on the effect obtained by applying the colloidal solution of the present invention to teeth.
The present invention has been completed on the basis of a methodology contrary to the prior art wherein efforts were made so that no water-insoluble or difficultly water-soluble precipitate ls formed.
Namely, the present invention has been completed on the basis of an idea that even when the water-insoluble or difficultly water-soluble precipitate is formed, the effect of the fluoride ion can be maintained as far as the particles thereof are fine. In fact, calcium and fluoride ions in amounts beyond ordinary solubilities of them were detected in a colloidal solution of calcium fluoride (fine particle solution of the present invention). When the colloidal solution is diluted with water, calcium fluoride is dissolved 2J}17918 - 2~

at a dissolution rate far higher than that of ordinary calcium fluoride to release fluoride ions.
An example of this phenomenon is given in Example 1.

Fxample 1 F ion Amount of CaF2 colloid (~0.22 to 0.65 ~m) 15 5 (~Fo2 c22olloid ~peptizer added) 100 20 CaF2 powder (1 to 2 ~m) 8 0.1 CaF2 powder (2 ~m ~) 8 0.1 Surprisingly, the colloidal particle was found to be able to be adsorbed on hydroxyapatite which is a main constituent of the tooth. Thus the effect of fluorine was exhibited not only for a short time of staying of the composition in the mouth but also lasted for a long period of time to retain the fluorine concentration in the mouth.
The stability of the colloidal solution was remarkably improved by adding the peptizer.
Example 2 gives the results of examination of the state of the colloid and fluorine uptake before 2r, 17~18 ~o ancl after the storage at room temperature for 6 months.
The colloidal solution was stable also to salts and surfactants usually incorporated into oral compositions. However, it was unstable when the pH was 5.0 or below or 9.0 or above.

[ test method ]
Calcium glucose-l-phosphate tetrahydrate and sodium fluoride are mixed with each other at a mole ratio of 1:2. Distilled water is added to the mixture to obtain a testing colloidal solution having a fluorine ion concentration of 2,000 ppm.
One gram of hydroxyapatite powder is treated with 10 ml of the solution and then washed with 40 ml of distilled water two times. Three ml of concentrated hydrochloric acid is added to the the powder to obtain its solution, followed by diluting it to a suitable concentration. An amount of the fluoride uptaken there is determined with the use of a fluoride ion-selective electrode. Results are shown below in Table.

3 ~ Z~`117918 _ C)~
rl ,Y ~ ~
O G) h ~ ~D O
G~ ~ ~ ~ ~ v d ~ O ~
h ~ h a5 0 h ~1 ~ ~ ~ Q, O
O O ~ ~~ r~ o ~A
~ tn~ ~ O
a) 4-1 . fd ~ '~
~ ~ h ,1 .C h O
.C ~ ~ ~1 3 tl. O
o O ~ O O
~ C
Q~ O h as u~ a) o ~ ~ ~ ~.
. . .
~1 ~~D ~ ~D
~ h 4 tn ~ o o ~ ~ ~ ~ a~
tJI ~ h ha) ~ 3 ~ Q) E~ h ~1 ~1 ~ (~ .,1 o a) ~ Q-~ ,C
G) m ~ ~ u~
~I h u~ C ~I C) Q
0 4~ (~ tJ' ~I h .,1 ~ t~ ~) ~1 ~ p~ U~
~ C h _ ~0 o ~ . ~
.
U~ O
~ o 8 ~o 1~:1 U) h Ql E~ Q~
~1 ~ .-1 ~ a) 'o '~ O ~ ~1 0 E~ v~
td ,1 ~ ~ O -~ ~
x a ~ ~ z ~ ~d - Z~7918 Further the effect of preventing actual teeth from decaying was confirmed.
In the experiment, a nondecayed human tooth was cut into three pieces, and the surface of each piece was polished and manicured, while leaving a part (1 x 1 mm) to be exposed to an acid in each piece.
These pieces were immersed in the colloidal solution of the present invention, a sodium fluoride solution, and distilled water, respectively, for 1 min and then delimed with an acid solution.
The colloidal solution and the sodium fluoride solution each contained 100 ppm of fluorine.
The acid solution was adding hydroxyapatite in a concentration of 50% of the saturation to 0.1 M
lactic acid, further adding 0.2% polyacrylic acid thereto and adjusting the pH to S.

. . .
Since the tooth generally becomes cloudy by the deliming, its acid resistance was judged from the extent of formation of white spots in the part exposed to the acid. The white spots were scarcely found in the part which had been treated with the colloidal solution before the exposure to the acid; considerable spots were found in the part which had been treated with distilled water before the exposure to the acid; and some spots were found in the part which 3 3 2~17918 had been treated with the NaF solution before the exposure to the acid. Thus an extremely high effect of the treatment with the colloidal solution of the present invention was confirmed.
In addition to the above-described colloidal fluoride solution of the present invention, similar effects can be obtained when other colloidal solutions containing other fluoride and peptizer according to the present invention are used. The state and storage stability of main colloidal fluoride solutions and fluorine uptake effect were examined in Example 3 and the results are summarized in the following table:

The above shown colloid solution was obtained in the same way as shown in Example 1, using the above shown method (ii), at a mole ratio of the peptizer to the cation to sodium fluoride of 1:1:2, having a fluorine ion concentration of 2,000 ppm in the solution. The solution was allowed to stand for 1 day before determination of properties.
The colloidal solution was filterèd through a Millipore filter having a pore size of 0.8 micron and the filtrate was centrfuged with an ultracentrifugal separater at 50,000 rpm at 15 degree C. Precipitates 3,~ ; 2qll791 ~o S l X ~1 ~ ~ Na~ I N N ~1 0 _I
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Zl`~179~8 found indicate colloidization. A fluorine amount in the colloidal particles is calculated by reducing a fluorine ion amount dissolved in the solution, determlned by the fluorine ion electrode, from the entire fluorine amount of the solution. A fluorine amount uptaken by the apertite is determined in the same way as shown in Example 1.
The combinations below the dotted line in the above table are not included in the present invention.
When zinc or tin was used, no colloid was formed.
When manganese was used, the fluorine uptake effect was similar to that of the control, though the colloid was formed.
Colloids superior to the fluorine-containing agents heretofore used were those having a fluorine content of the colloidal particles of at least 10~.
The colloid containing strontium in Example 3 had a fluorine content of the colloidal particles of 18% and fluorine uptake of 6 times as high as that of the control ànd, therefore, it is superior to the fluorine-containing agents heretofore used.
Although polyphosphoric acid serves as the peptizer, it does not seem to be adsorbable on teeth.
The fluorine intakes of the controls were far lower than those of the colloidal solutions of the 2~-~17918 present invention.
The colloidal solution of the present invention is used singly or in combination with other substances so as to have a fluorine content of 10 to 100,000 ppm, or the composition thus formed can be supported on another carrier to form an oral composition usable for preventing the tooth from decaying.
Application Examples of the colloidal solution of the present invention will now be described.

Example 4 (mouth-wash) glycerol 20.0% by weight sorbitol 24.0% "
propylene glycol 3.0% "

polyoxyethylene 1.0% "
polyoxypropylene glycol methyl p-hydroxybenzoate0.1% "
saccharin sodium 1.0% "
flavor o,g colloidal solution tNote 1) 50.0%

100 . o%
Note 11 A 3 mM solution of calcium chloride or strontium chloride was prepared and an equal amount of 6 mM sodium fluoride was added to this solution. lmmediately thereafter, 1 M slurry of disodium glycerophosphate or ~17918 disodium ribose 5-phosphate was added dropwise thereto to make the mixture transparent. The transparent mixture was left to stand for 1 h and used for the formulation.
Example 5 ~tablets for mouth-wash) (Note 1) dry fluoride gel (Note 2) 25.0% by weight common salt 68.0% "
hydroxyethylcellulose 1.0% ;' saccharin sodium 5.0% "
flavor 1.0%

100 . 0% "

Note 1) A tablet weighing 5 g is dissolved in 100 m~
of water or hot water for use in mouth-washing.
Note 23 12 g of aluminum chloride and 18 g of disodium glucose l-phosphate tetrahydrate were added to 4.2 g of sodium fluoride.
100 mQ of water was added to the mixture and stirred to give a transparent mixture.
It was centrifuged with a centrifugal separator (200,000 G) for 10 h and a precipitate thus formed was dried and pulverized.

Example 6 (tooth paste) --3 & Z~ 17~

abrasive (Note 1) 40.0% by weight glycerol 20.0% "
sorbitol 24.0% "
propylene glycol 3.0% "
hydroxyethylcellulose 1.0%
sodium lauryl sulfate 1.0% "
methyl p-hydroxybenzoate 0.1% "
saccharin sodium 1.0% "
flavor o.g% ~
dry fluoride gel (~ote 2)1.0% "

100 . 0% ~

Note l) Either calcium hydrogenphosphate dihydrate or calcium pyrophosphate was used.
Note 2) The same as the dry gel in Note 2) of Application Example 2.

The oral composition will be explained in reference to its tests and examples.

2~-1179~8 3g The effect of the present invention will be further illustrated by the following Experimental Examples of the production of the colloidal fluoride which can be contained in the oral composition of the present invention and Experimental Examples of evaluation of its capacity of supplying fluorine to the tooth.
Experiment 1 [dissolution state of solution of mixture of fluorine, calcium and peptizer and colloid formation]
A mixture of predetermined amounts of sodium fluoride as the fluorine source and calcium glucose l-phosphate as both the calcium source and peptizer source, or calcium chloride as the control was dissolved in purified water to give a predetermined mixing ratio. The solution was left to stand at room temperature for one day and a precipitate thus formed was observed with naked eyes. The mixing molar proportions of the fluoride ion, the calcium ion and the glucose l-phosphate ion were 0.1 to 10/1/:
1. The total fluorine concentration in the solution was 50 to 5,000 ppm.

~ ~ Z~17918 -o ',+++++, ~ , 4~ ~ . ,,, ,++
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. ~ I I I + + + I ~ Q) 0 rl + ~1 ~0 ~ o a~
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O ~ O ~ ~ U~ ~ + + +
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~ ;~ Z~17~18 The particle diameter in a solution having the best dissolution state (F/Ca/GlP = 2/1/1) and having a fluorine concentration of 1500 ppm was determined with a dynamic light scattering measurement device (mfd. by Otsuka Denshi) to reveal that the particles were extremely fine colloidal ones having a mean particle diameter of 12.5 nm. The calcium ion concentration was measured with an ion-selective electrode (mfd. by Orion) to find that the free calcium ion concentration therein was less than 1 mM.
Namely, substantially no free calcium ion was present therein. This fact suggests that calcium present in the solution is substantially in the form of colloidal particles and is no more in the form of an ion.
In another solution wherein Fa/Ca was 0.1 to 1/1, the calcion ion concentration was reduced as the total fluorine concentration was increased. In still another solution wherein F/Ca was 4 to 10/1, substantially no calcium ion was present. Although a small amount of the precipitate is found in the solution containing glucose l-phosphate, its amount is smaller than that of the precipitate formed in the control solution free from glucose l-phosphate.
It is evident from this fact that at least part of 2~7918 calcium forms colloidal particles in the presence of glucose l-phosphate.
Experiment 2 [effect of fluoride colloid of supplying fluorine to tooth]
In this experiment, hydroxyapatite (a calcium phosphate constituting at least 90% of the enamel of the tooth) powder was used as a model tooth.
1 g of the powder was dispersed in 10 mQ of deionized water and 30 mQ Of a colloidal fluoride solution (F/Ca/GlP = 2/1/1) having a varied concentration was added to the dispersion. The mixture was treated at room temperature for one minute and then centrifuged at 3,000 rpm to give hydroxyapatite powder, which was then washed by dispersing in pure water. This procedure was repeated again. The powder was dissolved in 3 mQ of concentrated hydrochloric acid and the solution was suitably diluted. The quantity of fluorine taken therein was determined with an ion-selective electrode.
Fig. 1 is a graph showing changes in the quantity of fluorine taken into hydroxyapatite when a colloidal fluoride solution or a sodium fluoride solution (control) was used and the total fluorine concentration in the solution was varied from 10 to 3,300 ppm.
It is apparent from the graph that when the fluorine 2~117918 concentration was adjusted to that of ordinary dentifrices or mouth-washes, the colloidal fluoride had at least 10 times as high fluorine-supplying capacity as that of sodium fluoride.
Experiment 3 [effect of colloidal fluoride of improving acid resistance of tooth]
A sound human tooth was vertically divided into three pieces, polished on the surface and were each coated with an oil-base paint in order to keep the tooth from the attack by an acid, while leaving a part (about 1 x 1 mm) of the enamel to form a window to be exposed to the acid. Then the sample tooth pieces were immersed in a colloidal fluoride solution (F/Ca/GlP
= 2/1/1) having a total fluorine concentration of 100 ppm, a sodium fluoride solution having a total fluorine concentration of 100 ppm, and deionized water (control), respectively, at room temperature for 1 min to treat the exposed surface of the enamel therewith. Then each sample was immersed in a 0.1 M
lactate buffer solution (pH: 5.0) at room temperature for 12 h to delime the exposed part of the enamel.
This procedure was continuously repeated six times.
Then the paint was removed and white spots (initial stage of tooth decaying) formed in the delimed part were observed. Thus it was found that the extent of - 2~i7918 the formation of the white spots were as follows:
sample treated with deionized water > sample treated with sodium fluoride > sample treated with colloidal fluoride. This fact indicated that the colloidal fluoride had an excellent effect of improving the .
acid resistance of the tooth. The above shown 0.1 M
lactate buffer is obtained by the following. One percent of Carbopol 907, tradename of polyacrylic acid, is adjusted at pH of 4Ø with lON NaOH. 40 ml of the liquid is mixed with 2 g of lactic acid and then distilled water to amount to 200 ml, adjusted at pH of 5.0 with 10N NaOH, to obtain an unsaturated liquid of apatite. 110 ml of the liquid is mixed with 0.22 g of hdyroxyapatite. The mixture is adjusted at pH of 5.0 with lN hydrochloric acid and 2il1'7918 centifuged, decanted. The decanted liquid is filterated wiht a Millipore filter having a pore ~ize of 1 micron to obtain saturated apatite solution. It is mixed equivoquantatively with the unsaturated apatite solution to obtain 0.lM lactate solution.

Experiment 4 ~peptizers]
In this experiment sodium fluoride, calcium chloride and each of the sodium salts of various saccharide derivatives were mixed together in a molar proportion of 2/1/1 so that the total fluorine concentration would be 500 ppm to give a solution.
One day after, the state of-the solution ~refer to Experiment 1) was observed with naked eyes and the effect of supplying fluorine (refer to Experiment 2) was ~valuated.

~ ~ ` 2~i7918 Table 2 Function of various saccharide derivatives as the peptizer Peptizer State of Supply formation) (mq/g) glyceraldehyde 3-phosphate . 1.2 ~-glycerophosphate _ 1.7 ~-glycerophosphate _ 3.1 erythrose 4-phosphate _ 2.2 ribose 5-phosphate _ 2.8 glucose l-phosphate _ 4.2 glucose 6-diphosphate _ 3.8 inositol monophosphate _ 2.5 inositol hexaphosphate _ 1.3 fructose l-phosphate _ 2.5 fructose 6-phosphate _ 1.6 fructose 1,6-diphosphate _ 1.0 ascorbic acid 2-phosphate _ 2.0 heptulose 7-phosphate _ 1.7 sucrose sulfate + 1.0 ascorbic acid 2-sulfate + 1.1 glyceric acid ~ 0.6 gluconic acid + 0.8 control (no peptizer used) ++ 0.3 ~ 7 2~17918 The above-described results indicate that not only glucose l-phosphate but also many kinds of saccharide derivatives act as the peptizer to form a colloidal fluoride in the same manner.
It is apparent from the above-described experiments that when a fluoride ion is reacted with a calcium ion in the presence of a particular saccharide derivative, the colloidal fluoride having an excellent effect of supplying fluorine to the tooth can be formed. It is necessary, however, that the total fluorine concentration in the solution exceed 8 ppm, since the fluorine concentration of a saturated calcium fluoride solution is about 8 ppm. When the total fluorine concentration is less than 8 ppm, calcium fluoride is dissolved and no colloidal fluoride can be formed.
Although the saccharide derivative used in the above-described experiment was the sodium salt, a calcium salt of the saccharide derivative can also be used if it is highly soluble in water. The calcium salts include calcium glucose l-phosphate, calcium glucose 6-phosphate and calcium fructose 1,6-diphosphate. When such a calcium salt is used, the incorporation of an additional water-soluble calcium salt is not always necessary.

~ & 2~17918 The colloidal fluoride solution can be used as an oral composition in various forms such as a dentifrice, a mouth-wash, a tooth coating agent, buccal tablets and chewing gum. Various bases and other medicinal ingredients usually incorporated into dentifrices, mouth-washes, agents to be applied to the tooth and buccal tablets can be also incorporated thereinto. However, when a compound having a strong chelating effect or an ingredient easily adsorbable on calcium phosphate is used, attention should be paid not to lose the effect of the colloidal fluoride, since it might destroy the colloidal fluoride or aggregate the colloidal particles to form a precipitate.

The following Examples of the composition of the present invention comprising the colloidal fluoride and effective in preventing the tooth from decaying with further illustrate the present invention, which by no means limit the invention.
Example 7 (toothpaste) Among the following ingredients, sodium fluoride and calcium glucose l-phosphate were first dissolved in purified water to form a fluoride colloid. Then other ingreidents were mixed with the colloid under deaeration to form a toothpaste. The effect of the ~ ~ 2a~791~

toothpaste of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
sodium fluoride 0.2% by weight calcium glucose l-phosphate 0.9~ "
tetrahydrate aluminum hydroxide35.0% "
hydroxyethylcellulose2.0%
sucrose fatty acid ester 2.5% "
fatty acid diethanolamide 0.5%
glycerol 10.0% "
70% sorbitol solution15.0% "
methylparaben 0.1% "
flavor 1.0% "
sodium saccharin 0.2% "
purified water a suitable amount -total 100.0% by weight Example 8 (toothpaste) Among the following ingredients, sodium fluoride and calcium glucose l-phosphate were dissolved in purified water to form a fluoride colloid. Then other ingredients were mixed with the colloid under deaeration to form a toothpaste in the form of a transparent gel. The effect of the toothpaste of 5~
Zd~l7918 preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3.
The results indicated an excellent effect thereof.
sodium fluoride 0.2~ by weight calcium glucose l-phosphate 2.0% "
tetrahydrate silicic acid anhydride25.0% "
polysodium acrylate1.0% "
hydroxyethylcellulose1.0%
sodium lauryl sulfate1.5% "
glycerol 10.0% "
70% sorbitol solution15.0% "
methylparaben 0.1% "
flavor 1.0% "
sodium saccharin 0.2% "
colorant a suitable amount purified water a suitable amount total 100.0% by weight Example 9 (toothpaste) Among the folloiwng ingreidents, potassium fluoride and calcium glycose 6-phosphate were dissolved in purified water to form a fluoride colloid.
Then other ingredients were mixed with the colloid under deaeration to form a toothpaste. The effect of the toothpaste of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
potassium fluoride 0.2% by weight calcium glucose 6-phosphate 2.0~ "
tetrahydrate calcium hydrogenphosphate 25.03 "
for dentifrice sodium carboxymethylcellulose 1.0% "
hydroxyethylcellulose1.0% "
soidum lauryl sulfate1.5% "
fatty acid diethanolamide 0.53 "
glycerol 10.0% "
70% sorbitol solution15.0% "
methylparaben 0.1% "
flavor 1.0% "
sodium saccharin 0.2% "
purified water a suitable amount total 100.0% by weight Example 10 (toothpaste) Among the following ingredients, sodium fluoride and calcium fructose 1,6-diphosphate were first dissolved in purified water to form a fluoride colloid.
Then other ingredients were mixed with the colloid under deaeration to form a toothpaste. The effect 5 ~ 2~I17918 of the toothpaste of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
sodium fluoride 0.2% by weight calcium fructose 0.5% "
1,6-diphosphate crystalline cellulose powder 15.0~ "
sodium carboxymethylcellulose 1.0% "
hydroxyethylcellulose1.0% "
sodium lauryl sulfate1.5~ "
fatty acid diethanolamide 0.5% "
glycerol 10.0% "
70% sorbitol solution15.0% "
methylparaben 0.1% "
flavor 1.0% '' sodium saccharin 0.2% "
purified water a suitable amount total 100.0% by weight Example 11 (mouth-wash) The following ingredients were mixed together to form a solution to be used as a mouth-wash. The effect of the mouth-wash of prevention the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an 2q~7918 excellent effect thereof.
sodium fluoride 0.2% by weight calcium glucose 1-phosphate 1.0% "
tetrahydrate glycerol 5.0% "

polyoxyethylene-hardened 0.5% "
castor oil ethanol 8.0% "
sodium saccharin 0.1% "
flavor 0.1% "
coloranta suitable amount purified watera suitable amount total 100.0% by weight Example 12 (mouth-wash) The following ingredients were mixed together to form a solution to be used as a mouth-wash. The effect of the mouth-wash of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
sodium fluoride0.2% by weight calcium glucose 6-phosphate 1.5% "
calcium chloride dihydrate 0.2% "
glycerol 5.0% "

polyoxyethylene-hardened 0.5% "
castor oil 5 ~ Z~17918 ethanol 8.0% by weight sodium saccharin 0.1% "
flavor 0.1% "
colorant a suitable amount purified water a suitable amount total 100.0% by weight Example 13 !mouth-wash) The following ingredients were mixed together to form a solution to be used as a mouth-wash. The ! effect of the mouth-wash of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
sodium fluoride 0.2% by weight sodium ribose 5-phosphate 2.0% "
calcium chloride dihydrate 0.3% "
glycerol 5.0%

: polyoxyethylene 0.8%
polypropylene glycol ethanol 8.0% "
sodium saccharin 0.1% "
flavor 0.1% "
colorant a suitable amount purified water a suitable amount total 100.0% by weight 5 ~ 2~-~17gl8 Example 14 (tooth coating agent) The following ingreidents were mixed together to form a viscous tooth coating agent. The effect of this agent of preventing to tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent effect thereof.
sodium fluoride 2.0% by weight calcium glucose l-phosphate 9.0~ "
tetrahydrate hydroxyethylcellulose 2.0%
flavor a suitable amount purified water a suitable amount total 100.0% by weight Example 15 (buccal tablets) 2 mol of sodium fluoride was mixed with l mol of calcium glucose l-phosphate powder and purified water was added to the mixture to form a colloidal solution having a high concentration, i.e., a solute concentration of 50 wt.%. Ethanol was added thereto in a volume equal to that of the solution to precipitate the fluoride colloid, which was recovered by filtration and dried to give a dry powder comprising fluoride colloid particles.
Then the following ingredients were mixed with ~ 6 Z~}1791~3 the powder, and the mixture was dry-tabletted to form buccal tablets. The buccal tablets thus formed were pulverized and dispersed in purified water to form a 20% dispersion. The effect of this dispersion of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3.
The results indicated an excellent effect thereof.

dry powder of fluoride 1.0% by weight colloid particles dextrin 10.0% "
! sodium saccharin 0.05%
citric acid 0.1% "
flavor a suitable amount purified water a suitable amount total 100.0~ by weight Example 16 (chewing gum) The dry powder comprising fluoride colloid particles prepared in ExamplelS was kneaded together with ingredients listed below under heating and the mixture was shaped into a chewing gum. 10 g of the chewing gum was finely broken in 50 mQ of purified water to form a dispersion. The effect of this dispersion of preventing the tooth from initial decaying was evaluated by the method employed in Experiment 3. The results indicated an excellent 2~791~

effect thereof.
dry pow~er of fluoride1.0~ by weight colloid particles gum base 20.0% "
corn syrup 20.0~ "
citric acid 0.1% "
flavora suitable amount sucrose powdera suitalbe amount total 100.0% by weight

Claims (29)

1. A colloidal solution comprising colloidal particles of a fluoride contained in water, wherein (i) the said fluoride is hardly soluble in water and is capable of forming a saturated water solution thereof having a fluorine concentration of 1 to 10,000 ppm and (ii) the colloidal particles have a particle size of 0.005 to 1 micron.

2. The solution as claimed in Claim 1, which further com-prise a peptizer that stabilizes the colloidal particles of the fluoride.

3. The solution as claimed in Claim 2, which comprises 1 to 100,000 ppm, based on the entire solution, of fluorine in the colloidal particles, 10 to 100 percent by weight of the fluorine contained in the entire solution being included in the colloidal particles.

4. The solution as claimed in Claim 2, in which the pep-tizer is selected from the group consisting of polyolphosphoric acids, polyolsulfuric acids, polyolcarboxylic acids and salts of these acids.

5. The solution as claimed in Claim 2, which comprises 1 to 95,000 ppm, based on the entire solution, of fluorine in the col-loidal particles, 10 to 95 percent by weight of the fluorine con-tained in the entire solution being included in the colloidal particles.

6. The solution as claimed in Claim 2, in which the col-loidal particles of the fluoride have a particle size of 0.01 to 1 micron.

7. A transparent colloidal solution comprising colloidal particles of a fluoride contained in water, wherein:
(i) the said fluoride has such a low solubility in water that a saturated water solution thereof has a fluorine concentra-tion of 1 to 10,000 ppm and the said fluoride is a member selected from the group consisting of calcium fluoride, aluminum fluoride, magnesium fluoride, barium fluoride, titanium fluoride, strontium fluoride, indium fluoride and lanthanoid fluorides;
(ii) the colloidal particles have a particle size of 0.005 to 1 micron and are stabilized in the solution by a peptizer; and (iii) the colloidal solution contains 1 to 95,000 ppm, based on the entire solution, of fluorine in the colloidal particles, while 10 to 95 % by weight of the fluorine contained in the entire solution is included in the colloidal particles and the remaining fluorine is dissolved in water.

8. The solution as claimed in Claim 7, which contains 150 to 60,000 ppm, based on the entire solution, of fluorine in the colloidal particles.

9. The solution as claimed in Claim 8, which has a pH of from about 5 to about 9.

10. The solution as claimed in Claim 9, wherein the fluoride is calcium fluoride.

11. The solution as claimed in Claim 7, 8, 9 or 10, wherein the peptizer is selected from the group consisting of saccharide phosphoric acids, saccharide sulfuric acids, saccharide carboxylic acids and water soluble salts of these acids.

12. A process for preparing a colloidal solution of a fluo-ride that is hardly soluble in water, which comprises:
mixing a water-soluble fluoride with a water-soluble cation salt to form precipitates and then adding a peptizer to the precipitates to produce col-loidal particles having a particle size of 0.005 to 1 micron in water.

13. A process for preparing a colloidal solution of a fluo-ride that is hardly soluble in water, which comprises:
mixing an aqueous solution of a water-soluble fluoride with an aqueous solution of a water-soluble cation salt to form precipitates, at least one of the two solutions containing a pep-tizer, to produce colloidal particles having a size of 0.005 to 1 micron in water.

14. A process as claimed in Claim 12 or 13, which further comprises removing water from the colloidal solution, thereby pre-paring colloidal particles.

15. Colloidal particles obtained by the process of Claim 14.

16. Colloidal particles obtained by removing water from the solution as defined in Claim 1.

17. The process as claimed in Claim 12 or 13, in which the water-soluble fluoride is a water-soluble hydrofluoric acid and the water-soluble cation salt is a water-soluble calcium salt.

18. The process as claimed in Claim 12 or 13, in which the peptizer is a saccharide selected from the class consisting of [A] a monosaccharide having (i) 3 to 10 carbon atoms and (ii) at least one acidic group selected from the class consisting of a phosphate group, a sulfate group and a carboxyl group in the mole-cule, [B] an oligosaccharide comprising 2 to 6 of the monosaccha-ride and [C] a polyhydric alcohol having 3 to 10 carbon atoms and falling in a saccharide.

19. An oral composition comprising an aqueous solution con-taining colloidal particles of a hardly water-soluble fluoride formed by a water-soluble fluoride and a water-soluble cation salt, wherein (a) the hardly water-soluble fluoride has such a low solubility in water that a saturated water solution thereof has a fluorine concentration of 1 to 10,000 ppm, (b) the colloidal particles have a particle size of 0.005 to 1 micron, and (c) the colloidal solution is stabilized by a peptizer.

20. An oral composition which is a tablet for making a mouth-wash liquid by dissolving in water and which comprises colloidal particles in a powder form prepared by removing water from the colloidal solution as defined in any one of Claims 2 to 10.

21. An oral composition which is a tooth paste comprising colloidal particles in a powder or gel form prepared by removing water from the colloidal solution as defined in any one of Claims 2 to 10.

22. An oral composition comprising a water-soluble fluoride, a water-soluble cation salt and a peptizer.

23. The composition as claimed in Claim 22, in which the fluoride is a water-soluble hydrofluoric acid and the salt is a water-soluble calcium salt.

24. The composition as claimed in Claim 22, in which the peptizer is a saccharide selected from a monosaccharide having 3 to 10 carbon atoms and one or more phosphate groups and/or sulfate groups and/or carboxyl groups in the molecule, an oligosaccharide comprising 2 to 6 of the monosaccharide and a polyhydric alcohol having 3 to 10 carbon atoms and falling in a saccharide.

25. The composition as claimed in Claim 22, which comprises 10 ppm or more of fluorine.

26. The composition as claimed in Claim 22, which comprises 10 ppm to 100,000 ppm of fluorine.

27. The composition as claimed in Claim 22, which comprises 150 ppm to 60,000 ppm of fluorine.

28. The composition as claimed in Claim 22, which comprises 1 mol part of the calcium, 0.01 to 100 mol parts of the fluorine and 0.01 to 100 mol parts of the saccharide.

29. The composition as claimed in Claim 22, which comprises 1 mol part of the calcium, 0.1 to 10 mol parts of the fluorine and 0.1 to 10 mol parts of the saccharide.