JPH0159251B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD This invention relates to oral science, and more particularly to an agent for treating dental caries. The medicament of this invention is intended for oral administration and can be used for the prevention and treatment of dental caries. Various caries prevention and treatment tablets containing sodium fluoride as an active ingredient are known (Farmocopeia romona 1972, p. 460, British
Pharmacopeia 1973, p. 431). Furthermore, dental caries prevention tablets are known. That is, Calcipot-F
(Arzneimittel-Verzeichnis 1982, Teil 1, Berlin, 1981 S.76), which tablets comprise calcium and fluorine compounds as active ingredients. The composition (g) of this drug is as follows. CaHPO ₄ 0.29 Calcium citrate 0.05 Calcium lactate 0.01 Satucarose 0.50 Lactose 0.047 Magnesium fluorosilicate 0.0024 Weight of one tablet 1 g The overall caries prevention effect of this tablet is limited. In this tablet, the concentration of fluorine, calcium, and phosphate ions in saliva is low, so there is a limit to increasing the resistance of hard and soft tissues, and there is also a limit to suppressing the caries-inducing effect of dental plaque. The main object of this invention is to provide an effective anti-caries agent that provides resistance to caries in the hard and soft tissues of the oral cavity. Another object of the present invention is to provide a medicament that suppresses the caries-inducing effect of dental plaque. The above and other objects of the present invention are characterized by comprising an active ingredient and a pharmaceutical diluent in a ratio of 1:23.5 to 24.5, wherein the active ingredient consists of sodium monofluorophosphate and an anti-caries ingredient; The components are extracted by the following method: treating the bone tissue with dilute mineral acids until the inorganic components and water-soluble proteins contained in the bone tissue are completely dissolved, separating the solution thus produced, and diluting this solution with water. and adding citric acid or its salt as a stabilizer, then neutralizing and drying this solution and containing the following ingredients (% by weight): calcium 2~ 6 Sodium 19-23 Potassium 0.04-0.18 Mineral acid anion 6-10.6 Orthophosphate anion 1.5-5.0 Water-soluble protein 1.0-5.0 Magnesium 0.05-0.2 Trace elements including fluorine, manganese, tin, zinc and iron 0.01-0.02 Citric acid Acid compounds (as citrate anion)
This is achieved by a caries treatment agent containing a total amount of 100. The anti-caries component described above can be prepared as follows. Bone tissue of a mammal, such as a cow or a pig, is immersed in a dilute mineral acid, such as 2-7% hydrochloric acid, and maintained with stirring until the water-soluble proteins and inorganic components in the bone tissue are completely dissolved. The solution thus obtained is then separated, for example by filtration and diluted 1:4 to 1:6 with water,
A stabilizer, such as citric acid or a salt thereof, is then added, for example in a ratio of 2:1 to 4:1. Next, this solution is neutralized with, for example, a sodium hydroxide solution to a pH of 6.5 to 7.5 while being continuously stirred. In this way, a liquid anti-caries component is obtained. For ease of transportation and storage, the anti-caries component is obtained as a dry product. For this purpose, for example, the liquid anti-caries component may be dried in a dryer [for example, a small Niro dryer].
Spray in an atomizer (Niro Atomizer),
Spray dry by protecting the temperature in the dryer between 70℃ and 90℃. The therapeutic agents of this invention are intended for oral administration in the form of tablets. One tablet contains 0.0065-0.0075g of sodium monofluorophosphate as active ingredient
It is preferable to contain 0.16 to 0.18 g of an anti-caries component. Preferred pharmaceutical fillers are starch or lactose. As mentioned above, the medicaments of this invention are administered in the form of tablets or pills. The tablets are white, odorless, and have a sweet taste. The tablets dissolve well in water and saliva. Tablets must be chewed before swallowing. Local therapeutic effects occur by chewing the tablet for 2-3 minutes. When swallowed, the tablet produces a general therapeutic effect,
It increases the resistance of hard and soft tissues in the oral cavity to caries and reduces the caries-inducing effect of dental plaque. The effect of the anti-caries agent of this invention will be compared with that of Calcippot-F. In the former case, the fluoride ion concentration increases by 6 to 7 times, the calcium ion concentration increases by 2 to 2.5 times, and the phosphate ion concentration increases by 2 times compared to the latter. The anti-caries action of the drug of this invention is twice that of calcipot-F. When treated with the drug of the invention, the permeability of enamel is reduced by one-third and the cariogenicity of dental plaque is reduced by two-fold compared to after treatment with Calcipot-F.
The anti-caries agent of this invention and its active ingredient were subjected to laboratory tests on animals and clinical tests on humans. A 3% solution of anti-caries ingredients was tested in comparison to a control. The test used 80 1 month old Wistar rats (40 were used for the test solution and the other 40
(one animal was used for the control group). All animals were fed the caries-inducing diet Stephan-580 and fed three times daily over the four-week study period.
The test solution was applied to the tooth for a minute. After the experiment was completed, the teeth were removed and the caries index was measured according to generally accepted methods.

[Table] A 3% solution of the caries-preventing ingredient of this invention was applied to children aged 7 to 7 years old.
When used for more than 1.5 years according to a twice-monthly dosing regimen in ~10 children, the caries prevention efficiency was determined by the relative decrease in the increase in the DMF-T index.
It is 44.1 to 53.7%, and according to the DMF-S index, it is 40.2%.
~58.0%, and according to the CRT-test data, the acid resistance of enamel increases considerably. 3 caries prevention ingredients in early stage caries treatment
The effectiveness of the % solution is high, and the positive effect of treatment, that is, the disappearance or reduction of mineral deficiency spots, is 72.4 to 84 in cases.
Stabilization of course was observed in 14-31.9%
No therapeutic effect was observed in 2-8% of cases. The effect of a 3% solution of anti-caries components in the treatment of hypersensitivity of hard tooth tissues was good, sufficiently enhanced sensation of the tooth neck was eliminated in 23.2-36.4% of cases. Clinical trials of anti-caries ingredients were carried out with a view to studying their preventive effects on children and pregnant women, as well as their effectiveness in the conservative treatment of focal mineral defects in tooth enamel. Cavity prevention ingredients
It was used in the form of a 1.5-3% dosing solution. Children aged 7-8 according to the results of epidemiological tests
They selected 176 people and divided them into two groups. 81 people in the first group received the anti-caries solution by application, and 95 people in the second group served as the control group. The solution was applied after pre-brushing the teeth with a sanitary toothpaste. The teeth were then isolated from saliva by lignin deposition and dried by blowing air. The solution was applied to all tooth surfaces by placing a well-soaked cotton ball on a flexible plastic spoon. Application time was 10 minutes for each jaw. After application, children were advised not to eat or drink for 2 hours. All subsequent biweekly applications were performed as described above. The DMF-T value of cavities was determined by preliminary observation of the oral cavity.
It was observed that a relatively uniform level of 1.12±0.13 to 1.30±0.13 was reached. The results of the application of the anti-caries solution are shown in Table 2. From this table it is clear that the increase in caries in the first group of children is 44.7% and 49.5% lower on the basis of DMF-T and DMF-S, respectively. In an analysis of the caries-preventing effect of the test ingredient on tooth types, it was confirmed that it was effective on first molars that had already erupted and on incisors that had erupted during the observation period. A solution of the test component was used to treat mineral defects in the teeth of 81 students aged 7-14. The students were divided into two subgroups according to the type of mineral deficiency. That is, Group 3a (total of 42 students): students with slowly progressing mineral deficiencies, and Group 3b (total of 39 students): students with rapidly progressing mineral deficiencies. Mineral defects were observed in a total of 229 teeth for students in group 3a and in a total of 248 teeth for students in group 3b.
table). The control groups are shown in the table as Group 1a and Group 1b corresponding to the above groups. In order to obtain a positive effect on the treatment of teeth with solutions of the tested components, in group 3a it is necessary to carry out 10-15 applications (on average), and in group 3b
It was necessary to perform 20-25 applications in groups. Remineralization treatment was more effective in treating slowly progressing mineral deficiency processes. Small spots (2 mm ² and 2-3 mm ² ) are
It decreased more rapidly than larger species and disappeared. Conservative treatment of rapidly progressing mineral defects in the teeth of students in group 3b was not effective. However, a linear relationship was observed between the treatment effect and the size of the spots (Table 4). In group 3a, a positive treatment effect, i.e., disappearance of spots, was observed in 193 out of 229 teeth (84% ± 2.4%), compared to 100 out of 270 teeth (36%) in the control group. A positive treatment effect was observed only for teeth (±2.9%). Stabilization processes were observed in 31 teeth (14% ± 6.23%) in group 3a and in 87 teeth (31% ± 2.8%) in the control group. Spot enlargement and cavity formation occur in group 3a.
It was observed in only 5 out of 229 teeth (2% ± 0.9%), but in the control group, it was observed in 92 out of 279 teeth (33
%±2.8%) of teeth. The difference between Group 3a and Group 1a (control group) was statistically significant (Table 4). In the treatment of rapidly progressing mineral defects in group 3b, a positive treatment effect occurred in 155 out of 248 teeth (63% ± 3.0%), compared to 33 out of 305 teeth in the control group. Spontaneous loss was observed only in (11% ± 1.8%) of the teeth. Section 3b
The mineral deficiency process was stabilized in 60 (24% ± 2.7%) teeth of students in the group. 33 of students in group 3b
Cavities were formed in mineral-deficient plaques of real teeth (13% ± 2.1%). There were statistically significant differences between the characteristics of Group 3b and Group 1b (control group) (Table 4). As a result, the average positive effect in treating rapid and slow mineral loss processes in tooth enamel was 73.5%.

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[Table] The solution of the ingredient having a caries preventive effect according to the present invention was tested on pregnant women. Epidemiological studies have found that in pregnant women, focal mineral defects in tooth enamel increase as the pregnancy progresses. In order to test the preventive effect against such a phenomenon, a solution of the ingredient having an anti-caries effect according to the present invention was applied to 69 pregnant women (group 1). The target group (group 2) was 64 pregnant women. The level of tooth damage due to focal mineral defects was 29-30% in both groups of pregnant women (gestational age 4-12 weeks).
It was hot. The average number of teeth damaged was 1.8±0.3. At the end of pregnancy, the increase in tooth enamel focal mineral defects in the control group was 64%, with an average of 5.23±0.7 teeth damaged. By using the ingredient of this invention having a caries-preventing effect in the first group of pregnant women, it is possible to not only prevent the formation of new focal lesions in the enamel, but also to stabilize the process of already existing focal lesions. I was able to do that. That is, no expansion of mineral defect nests or formation of cavities was observed. The anti-caries agent of this invention was prepared in tablet form and its effect on basic functions of animals was tested by acute and chronic tests. Acute tests were conducted in white mice and rats. Chronic studies were conducted in rats;
This study was conducted using guinea pigs and coin dogs. That is, the experiment was conducted using 4 animal species. By conducting toxicity tests, biochemical tests, and histological tests using various experimental methods, it was confirmed that the drug of this invention has no toxicity. The acute toxicity of a 30% aqueous suspension of the anti-caries component of this invention was determined using female and male white mice weighing 15-31 g. Test animals, 6000mg/Kg,
8000mg/Kg, 13000mg/Kg, 14000mg/Kg, 15000
mg/Kg and 16000 mg/Kg were administered orally using a metal probe. It was not possible to administer a larger amount. Animals were observed for 10 days after administering the anti-caries agent. It was not possible to determine the LD ₅₀ since no animals died even at the maximum dose that could be administered. In 2 mice out of all the animals tested (6 animals), tremor and temporary paralysis of the hind legs were observed for 5 minutes after administration of 16,000 mg/Kg of the anti-caries component. There was no change in animal behavior at lower doses. Experiments have shown that the anti-caries components of this invention have low toxicity levels when administered orally in tablet form. The acute toxicity of the anti-caries component was tested using male and female rats weighing 90-110 g. 30% of this ingredient
14500mg/Kg and 16000mg/Kg as aqueous suspension
were administered at a dose of After this period the animals were fed normal chow. There were no dead animals. During the first 2-3 hours the animals became fatigued and sluggish. It was not possible to determine the LD ₅₀ since no animals died even at the highest dose. It was concluded that the anti-caries component of this invention has low toxicity upon oral administration. The chronic toxicity of this ingredient was tested in young guinea pigs, rats and coin dogs. This ingredient had no effect on the general condition and growth of the animals. Blood tests (i.e. red and white blood cell counts,
The results of hemoglobin level, measurement of erythrocyte sedimentation rate, and differential blood count) and biochemical analysis of the blood and urine of the test animals did not show any pathological changes. Even if the anti-caries component of this invention is orally administered over a long period of time, the cardiovascular system, endocrine system,
and hematopoietic organs were not affected. No pathological changes were observed in the organs of the killed animals. It is also important that the anti-caries component of this invention is non-irritating and non-allergenic. The effects of the anti-caries component of this invention on humans,
It was compared with that of Calcipotto-F. The transfer of the active ingredients in the tablets to saliva was investigated by analyzing the saliva of 20 stomatology school students immediately after chewing Calcipot-F tablets and tablets containing the anti-caries component of this invention. The content of ionized fluorine and water-soluble fluorine was measured using a fluorine-selective electrode. The amount of phosphorus was determined by spectroscopic analysis. Ca content was determined by atomic absorption spectrometry. The effects of the above anti-caries agents on the permeability of ^Ca45 in enamel were investigated in canine teeth of dogs 2 to 4 years old.
Twenty-four bottles were tested by applying lozenges prepared from both drugs once for 30 minutes. Transmittance (%) was calculated compared to a control, ie, a canine tooth to which no drug was applied. The anti-caries effects of the two drugs, the transfer of fluorine compounds to the enamel surface layer, and the acid resistance of enamel were tested using 75 4-week-old Wistar rats. The two test groups consisted of 25 animals each. The other 25 animals served as a control group. All animals were fed the cariogenic diet Stephan-580 for 4 weeks. A suspension of calcipato-F and a suspension of the anti-caries component of this invention were added to a suspension of 60 to 90
It was applied to the teeth of the animals of the first and second test groups for a period of seconds. Application was done using a small brush. At the end of the experiment, the teeth were removed and the caries index was measured according to routine methods. The fluorine content in the enamel surface layer was determined electrochemically by biopsy. The acid resistance (CRT test) of enamel was determined by the Muhlemann and Wolgensinger method (Muhlemann, Wolgensinger, Helv.odonf., Acte, 1959, 3, 35).
~38). For this purpose, the upper incisors of rats were used, while the molar teeth were used to test the anti-caries effect of Calcipot-F and the drug of this invention, and to test the transfer of fluorine into the enamel. The caries-inducing effect of dental plaque was tested on 45 people who volunteered for the experiment. Of these, 30 people were divided into two test groups of 15 people each. The experiment was carried out using the Hardwick method (Hardwick, Brit.dent.,
(1960, 108, 255-260). Prior to the experiment, subjects were instructed not to brush their teeth for 24 hours. The control group consisted of 15 people. Inhibition of the acid-producing microflora of dental plaque was tested on the same 45 volunteers who were administered tablets of Calcipot-F and tablets containing the anti-caries components of this invention. The tablets were chewed thoroughly. Appropriately measured plaque samples were successively diluted with physiological saline solutions and analyzed. Resistant and selective liquid media and nutrient agar media were used to culture Streptococcus and Lactobacteria isolated from dental plaque. Quantitative evaluation was performed based on microbial titer. We selected 30 patients with similar symptoms in the early stages of gingivitis, measured the opsono-phagocytic index and the lysozyme content in saliva, and compared them with calcipot-F and the anti-caries of this invention. The anti-inflammatory effects of the ingredients were compared.
Some patients received the former, others the latter. The anti-inflammatory effect was evaluated according to a conventional method. Staphylococcus aureus isolated from components in the groove between teeth and gums was used as a test bacterium. Measure the total number of prey microorganisms per inoculation,
The arithmetic mean per leukocyte was then calculated and expressed as an opsonopathogen index. Lysozyme activity is an indicator of local protective factor status. This activity was measured 90-120 minutes after breakfast in mixed saliva by radial diffusion in biphthalate agar. Lysozyme level is mg/ml
Expressed as The test results are shown in Tables 5 and 6.

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[Table] Analysis of the above data shows that in the case of the anti-caries ingredient of the present invention, the concentration of active ingredients in the oral cavity, that is, fluorine compounds and phosphoric acid-calcium salts, is 2 to 7 times higher than in the case of Calcipot-F. Shown. When a tablet of the anti-caries component of this invention is administered to a patient, the permeability of enamel to Ca ⁴⁵ is reduced by about 30%, thereby preventing the permeation of the enamel from saliva into the hard tissues of the tooth. The anti-caries action of the drug according to the invention is three times higher than that of calcipot-F. In the drug of the invention, compared to Calcippot-F, the penetration of the active ingredients, especially fluorine, into the tooth tissue is 2.5 times higher and the acid resistance of the enamel is 80% higher. Due to the reduction in the titer of acid-producing microflora, the caries-inducing effect of dental plaque is greatly reduced. By administering tablets of the anti-caries component of this invention to a patient, the opsonopathogenic index does not differ from normal physiological levels. At the same time, the drug of the invention does not affect natural protective factors, as shown by the high content of lysozyme in saliva. The anti-caries agent of this invention can be made into tablets according to conventional methods. The anti-caries component contained in the drug can be prepared as follows. Inject mineral acids into bone tissue. The tissue is dissolved in mineral acid and stirred so that the inorganic components and water-soluble proteins contained in the bone tissue are completely dissolved. Separate the solution and dilute with water. Add citric acid or its salt to this solution and neutralize it. This solution is then sprayed in a drying chamber to obtain a dry product convenient for storage and transportation. The product is a white, amorphous, odorless powder with a salty taste. It is highly soluble in water, slightly soluble in 95% ethanol, and almost insoluble in ether. The daily dose of this drug is 0.0065 to 0.0075 g of sodium monofluorophosphate, and 0.16 g of the anti-caries ingredient of this invention.
~0.18g. The drug will be administered daily for 250 days. Tablets must be chewed before swallowing. The anti-caries agent of this invention has no side effects. There are no contraindications to the use of this drug.

Claims (1)

[Claims] 1. A mixture of sodium monofluorophosphate and an anti-caries component as an active ingredient, and a pharmaceutical diluent,
The ratio of the active ingredient to the diluent is 1:23.5 to 24.5.
The anti-caries component is prepared by the following method: treating the bone tissue with dilute mineral acid until the inorganic components and water-soluble proteins contained in the bone tissue are completely dissolved, and using the solution thus produced. It was prepared by separating, diluting this solution with water and adding citric acid or its salts as a stabilizer, then neutralizing this solution and drying and its components (by weight %), Calcium 2-6 Sodium 19-23 Potassium 0.04-0.18 Mineral acid anion 6-10.6 Orthophosphate anion 1.5-5.0 Water-soluble protein 1.0-5.0 Magnesium 0.05-0.2 Fluorine, manganese, tin, zinc and iron Trace elements included: 0.01-0.02 Citric acid compound (as citrate anion)
A caries treatment agent characterized in that the total amount is 100%. 2 Sodium monofluorophosphate 0.0065-0.0075
2. The therapeutic agent according to claim 1, which is a tablet comprising an active ingredient consisting of g and 0.16 to 0.18 g of a caries-preventing ingredient. 3. The therapeutic agent according to claim 1 or 2, wherein the pharmaceutical diluent is a filler selected from the group consisting of starch and lactose.