RU2423119C2 - Therapeutic and preventive medication for dental enamel - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of dentistry and represents therapeutic and preventive medication for dental enamel, which is characterised by the fact that it contains histidine 0.001-1.0%, lysine - 0.01-2.0%, arginine - 0.1-5.0%, each of said amino acids from total weight and distilled water - 20-90% of total weight.

EFFECT: invention makes it possible to prevent caries and normalises exchange processes in solid dental tissues.

21 cl, 5 dwg

Description

The invention relates to dentistry, and in particular to means for the prevention of dental caries.

State of the art

The problem of preventing the development of caries, despite the efforts made by both dentists and pharmaceutical companies specializing in the production of hygiene daily care products and dentistry medicines, remains very relevant.

The main way to prevent caries at the present time is to increase the content of fluorine and its compounds in these products, foods, and drinking water. For example, in the USA, in order to combat tooth decay, fluoridation of drinking water is used and with a certain decrease in the incidence rate, the problem remains quite serious.

Thus, the problem of successful caries prevention even in the most developed countries remains one of the main health problems. Data from the World Health Organization suggests that the economic costs of treating dental caries exceed the costs of preventing and treating common diseases such as coronary heart disease, arterial hypertension, or stroke.

Moreover, the use of fluoride compounds, as time has shown, is not a panacea and can lead to a number of diseases, such as fluorosis, even at the doses that are used today. The consumption of water with a high fluorine content (over 1-1.2 mg / l), food with an excessive content of fluoride compounds leads to a retention of fluoride salts in the bones and tissues of the teeth with the replacement of soluble calcium compounds by insoluble calcium and fluorine compounds, which leads to structural changes bone tissue (osteosclerosis), leading to bone deformation, calcification of the ligamentous apparatus.

Thus, the problem of creating a drug that can reduce the content of fluoride compounds without reducing the anticaries effect remains very relevant.

One of the most promising ways is the use of amino acids as a source of a biologically active antimicrobial agent, which also contributes to the regeneration of damaged tissues that are prone to initial demineralization by pathogenic microflora of various etiologies.

Recently, the use of amino acids as an alternative to antibiotics has gained sufficient distribution for a wide range of therapeutic diseases in general and in cariesology in particular.

A patent is known in which a phosphopeptide compound with a sequence of amino acids is described as an anti-carious preparation. This composition includes phosphopeptides selected from the group consisting of the ABCDE phosphopeptide sequence, where A, B, C, D and E are independently phosphoserine, phosphoterionine, phosphotyrosine, phosphohistedine, glutamate and aspartate, phosphopeptides have ABCDE sequences, where A, B and C are independent phosphoserine, phosphoterionine, phosphothyrosine and phosphogistedine, and D and E are independent phosphoserine, phosphoterionine, glutamate and aspartate, while the phosphopeptides have ABCDE sequences, where A, B and C are phosphoserine and D, and E are glutamates, and the phosphopeptides have both Glu-Met-Glu-Ala-Glu-Pse-Ile-Pse-Pse-Pse-Glu-Glu-Ile-Val-Pro-Asn-Pse-Val-Glu-Glu-Lys, phosphopeptides have Glu-Leu- Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-Ile-Val-Glu-Pse-Leu-Pse-Pse-Pse-Glu-Glu-Ser-Ile-Thr-Arg, phosphopeptides have Asn-Thr sequences Met-Glu-His-Val-Pse-Pse-Pse-Glu-Glu-Ser-Ile-Ile-Pse-Gln-Glu-Thr-Tyr-Lys, phosphopeptides have the sequence Asn-Ala-Asn-Glu-Glu- Glu-Tyr-Ser-Ile-Gly-Pse-Pse-Pse-Glu-Glu-Pse-Ala-Glu-Val-Ala-Thr-Glu-Glu-Val-Lys, phosphopeptides have the sequence Glu-Gln-Leu-Pse -Pth-Pse-Glu-Glu-Asn-Ser-Lys and their salts (1).

However, the use of peptides as one of the biologically active substances related to hormones requires special care and can lead to irreversible consequences. In addition, the technology for producing phosphopeptides is quite complex and expensive and is implemented using genetic engineering or by chemical means.

A patent application is also known in which a biocompatible polymer film made of a hydrophobic and hydrophilic layer including a source of fluorion, an antimicrobial component and excipients is used for the prevention and treatment of caries, as well as tooth hyperesthesia, characterized in that it additionally contains calcium compounds and phosphorus-containing compounds while sources of calcium, phosphate and fluorion are included in the hydrophilic layer of the film, while it contains organic fluorosoder as sources of fluorine ions The living compounds are fluorides of quaternary ammonium compounds of type N ₄ F, quaternary ammonium compounds with perfluoroalkyl groups, polycationic polymers containing fluorions, fluorophosphates, fluorooctanates of ammonium compounds, water-soluble amino acid complexes with metal fluorides (2).

A patent is also known in which:

1. A stable soluble complex of calcium phosphate, the preparation of which includes:

(i) preparing a solution of phosphopeptides, the phosphopeptides comprising the amino acid sequence Ser (P) -Ser (P) -Ser (P) -Glu-Glu (sequence 5); (ii) mixing the resulting solution in an alkaline medium with calcium ions and inorganic phosphate to obtain a mixture; and (iii) separating the complex from the alkaline mixture.

2. The complex according to paragraph 1, where the pH level is approximately 9.

3. The complex according to paragraph 1, where the amino acid sequence is selected from the group consisting of:

Gln ₅₉ -Met-Glu-Ala-Glu-Ser (P) -II-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ile-Val-Pro-Asn-Ser (P) - Val-Glu-Gln-Lys ₇₉ α (59-79) (sequence 1);

Arg ₁ -Glu-Leu-Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-Ile-Val-Glu-Ser (P) -Leu-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser-Ile-Thr-Arg ₂₅ β (1-25) (sequence 2);

Asn ₄₆ -Ala-Asn-Glu-Glu-Glu-Tyr-Ser-Ile-Gly-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser (P) -Ala-Glu-Val -Ala-Thr-Glu-Glu-Val-Lys ₇₀ α ₂ (46-70) (sequences 3) and

Lys ₁ -Asn-Thr-Met-Glu-His-Val-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser-Ile-Ile-Ser (P) -Gln-Glu-Thr -Tyr-Lys ₂₁ α ₂ (1-21) (sequence 4).

4. The complex according to paragraph 3, where the amino acid sequence includes:

- Gln ₅₉ -Met-Glu-Ala-Glu-Ser (P) -II-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ile-Val-Pro-Asn-Ser (P) -Val-Glu-Gln-Lys ₇₉ α (59-79) (sequence 1).

5. A stable, soluble complex of calcium fluoride phosphate, obtained as follows:

(i) preparing a solution of phosphopeptides, the phosphopeptides comprising the amino acid sequence Ser (P) -Ser (P) -Ser (P) -Glu-Glu (sequence 5); (ii) mixing in an alkaline medium calcium ions, inorganic phosphate and fluorine ions to obtain a mixture; and (iii) separating the complex from the resulting mixture.

6. The complex according to paragraph 5, where the pH of the alkaline medium is approximately 9.

7. The complex according to paragraph 5, where the amino acid sequence is selected from the sequence consisting of:

Gln ₅₉ -Met-Glu-Ala-Glu-Ser (P) -II-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ile-Val-Pro-Asn-Ser (P) - Val-Glu-Gln-Lys ₇₉ α _s1 (59-79) (sequence 1);

Arg ₁ -Glu-Leu-Glu-Glu-Leu-Asn-Val-Pro-Gly-Glu-Ile-Val-Glu-Ser (P) -Leu-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser-Ile-Thr-Arg ₂₅ β (1-25) (sequence 2);

Asn ₄₆ -Ala-Asn-Glu-Glu-Glu-Tyr-Ser-Ile-Gly-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser (P) -Ala-Glu-Val -Ala-Thr-Glu-Glu-Val-Lys ₇₀ α _s2 (46-70) (sequences 3) and

Lys ₁ -Asn-Thr-Met-Glu-His-Val-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ser-Ile-Ile-Ser (P) -Gln-Glu-Thr Tyr-Lys ₂₁ α _s2 (1-21) (sequence 4).

8. The complex according to paragraph 7, where the amino acid sequence contains:

Gln ₅₉ -Met-Glu-Ala-Glu-Ser (P) -II-Ser (P) -Ser (P) -Ser (P) -Glu-Glu-Ile-Val-Pro-Asn-Ser (P) - Val-Glu-Gln-Lys ₇₉ α (59-79) (sequence 1);

9. A method of preparing a stable, soluble complex of calcium phosphate, which consists in:

(i) preparing a phosphopeptide solution, wherein the phosphopeptides include the amino acid sequence Ser (P) -Ser (P) -Ser (P) -Glu-Glu (sequence 5); (ii) mixing the resulting solution with calcium ions and inorganic phosphate at a pH of about 7 to obtain a mixture; (iii) filtering the resulting mixture to obtain a residue and drying the residue to isolate the complex.

10. The method according to paragraph 9, where the preparation of phosphopeptides comprises mixing the solution with fluoride ions in addition to calcium ions and inorganic phosphate.

11. A stable, soluble complex of calcium phosphate, which is obtained in accordance with the process according to paragraph 9.

12. A stable, soluble complex of calcium phosphate, which is obtained in accordance with the process according to paragraph 10.

13. The means of delivery of the complex according to paragraphs 1, 5, 11 or 12 to a specific place for the localization of calcium ions and phosphate complex.

14. A means of delivery of the complex, which may be toothpaste, toothpowder, liquid dentifrice, mouthwash, tablets, chewing gum, dental paste, gum massage cream, rinse tablets and food products.

15. The means of delivery of the complex according to paragraph 14, where the food product is a dairy product.

16. A method of treating or preventing dental caries or tooth decay, including applying the complex according to paragraphs 1, 5, 11 or 12 to teeth or gums, depending on the need.

17. A drug, including:

(i) the complex according to paragraph 1, 6 and

(ii) a drug carrier or complex delivery vehicle.

18. The drug according to paragraph 17, where the complex is present in an amount sufficient to re-mineralize the teeth or to inhibit the development of caries or tooth decay.

19. The drug according to paragraph 17, where the complex is present in an amount sufficient to promote the absorption of calcium in a subject suffering from a condition associated with calcium loss, calcium deficiency or calcium malabsorption.

20. The drug according to paragraph 19, where the condition of the subject is osteoporosis or osteomalacia.

21. The drug according to paragraph 17 also includes food products.

22. The drug according to paragraph 21, where the food products are dairy products.

23. The drug according to paragraph 17 is a dentifrice.

24. The drug according to paragraph 23, wherein the dentifrice is selected from toothpaste, toothpowder, liquid dentifrice, mouthwash, tablet, chewing gum, toothpaste, gum massage cream and rinse tablets.

25. A method for re-mineralizing teeth or for inhibiting the development of caries or tooth decay involves the use of a sufficient amount of the complex according to paragraph 1, 5, 11 or 12, if necessary.

26. A method for improving calcium absorption in a subject suffering from a condition associated with calcium loss, calcium deficiency or calcium malabsorption includes the use of a sufficient amount of the complex according to paragraph 1, 5, 11 or 12.

This invention is taken as a prototype (3).

The main disadvantages of this invention is the complexity of its composition and manufacture. The calcium phosphopeptide complex contains large peptide sequences of numerous amino acids in bound form, which does not provide antibacterial resistance.

Such a complex complex, which includes almost the entire sequence of amino acids, will affect the enamel of the teeth of different patients in completely different ways, depending on their age, state of health, etc.

In addition, all of the above therapeutic formulations contain, in one form or another, fluorine or phosphorus compounds.

Recent studies conducted by the authors of the application have shown that the permeability of tooth enamel depends on age: tooth enamel in children is an enamel substance that contains a sufficiently large number of enamel tubules, which are filled mainly with essential amino acids: histidine, lysine, arginine. It is these acids that are the basis of the cationic protein, the effect of which is associated with the ability to break down the proteoglycans of the bacterial wall, that is, the saturation of tooth enamel tissues with these amino acids prevents the development of the carious process.

With age, the number of enamel tubules decreases, the content of these amino acids, which inhibited the growth of pathogenic microflora, sharply decreases. This is one of the causes of caries (4).

The technical result to which the claimed invention is directed is to create a gel composition of a therapeutic and prophylactic agent for tooth enamel, a therapeutic and prophylactic solution for rinsing, a therapeutic and preventive film for tooth enamel with a complex of essential amino acids that are not synthesized by the body, during the interaction of which it is synthesized cationic protein providing an antimicrobial barrier to tooth enamel.

Disclosure of invention

The present invention allows to prevent the appearance of caries on the teeth and normalize metabolic processes in the hard tissues of the teeth.

It is believed that the surface of the enamel has indentations of bacterial origin. But in fact, rounded formations on the surface of enamel with a diameter of up to 3 microns are the beginning of tunnels, the diameter of which varies from 1 to 3 microns, passing through the entire thickness of the enamel and S-shaped bends along the bundles of enamel prisms. In milk teeth, the number of enamel tunnels with a diameter of 1-2 microns is large and they are characterized by a uniform distribution over the surface of the enamel. With age, the number of enamel tunnels decreases, the uniformity of the location on the tooth enamel surface is lost (5).

Enamel tunnels are filled mainly with organic matter and play an important role in the exchange processes between the oral fluid through the enamel and dentin and the biological fluids of the tooth pulp, contributing to mineralization processes, regulating the enamel permeability for large molecular substances and microorganisms. This is also indicated by the presence of the largest number of enamel tunnels during the maturation period of tooth enamel, which is characterized by intense metabolic processes.

To study hard tooth tissues, studies were carried out using an automatic scanning electron microscope with magnification up to 5000 times (SEM) and using X-ray spectral microanalysis (RMA), with the identification of the distribution of macro- and microelements in qualitative and quantitative terms using color planar spectrograms.

The drawings show:

In Fig.1 - the surface of the enamel of the tooth with an increase of 1000 times, A - enamel tunnel,

Figure 2 - the surface of the enamel of the tooth with an increase of 5000 times, A - enamel tunnel.

Figure 3 - the enamel surface of a milk tooth with a magnification of 500 times, A - enamel tunnel.

Figure 4 - a section of tooth enamel with a magnification of 1000 times, A - enamel tunnel, B - enamel.

Figure 5 - tooth section, enamel-dentin border with an increase of 3,000 times, B - enamel, C - enamel bridge, C - dentin.

Studies using the SEM of the enamel-dentin border region at a magnification of 5,000 times revealed structural penetration of enamel into dentin in some of its sections to a depth of 5-8 μm, a width of 5-8 μm with the preservation of such important components of its structure as enamel tunnels. These formations of enamel penetration into dentin are called enamel bridges. In each enamel bridge there are 5-7 enamel tunnels, their density is higher than in the enamel, and the diameter is less - 0.5-1.5 microns.

A number of processes of odontoblasts penetrate precisely into the enamel tunnels of enamel bridges, where the exchange of substances between enamel and dentin is carried out. An indirect confirmation of the presence of these structures is the data on the change in the structure of enamel during caries, namely, a violation of the course of enamel tunnels and a loss of clarity of enamel bridges are determined.

Based on this, for the effectiveness of preventive measures against caries, it is necessary to take into account the chemical composition of the hard tissues of the teeth, as well as their structural and metabolic characteristics.

In the study of tooth sections removed by orthodontic indications using the developed modified histochemical technology for protein identification using bromphenol blue at a pH of 8.2, the presence of cationic protein and a set of its constituent amino acids were discovered in the tooth enamel and dentin, allowing metabolic processes to be realized and carry out a barrier antimicrobial function.

The cationic protein content in enamel structures is significant; 0.3559 + 0.01, σ = 0.119, in the nearby dentin, the corresponding values were: 0.1528 + 0.004, σ = 0.045.

It was found that enamel caries resistance depends on the content of not only inorganic substances, but also cationic protein. And for the synthesis of a cationic protein, essential amino acids, such as histidine, lysine and arginine, are needed. The protein network, surrounding apatites, also prevents the contact of acid with apatite and softens its effect.

The essence of the invention is a therapeutic and prophylactic agent for tooth enamel containing amino acids, which is characterized in that it contains histidine - 0.001-1.0%, lysine - 0.01-2.0%, arginine - 0.1-5.0% , each of these amino acids from the total mass, in combination with a set of components from those of some of the substances listed below:

- distilled water - 20-90%,

- sodium carboxymethyl cellulose - 0.5-10%,

- glycerin - 0.5-40%,

- potassium chloride - 0.1-10%,

- calcium glycerophosphate - 0.5-10%,

- calcium gluconate - 0.1-5%,

- calcium orthophosphate - 0.1-3%,

- zeolite 0.1-3%,

- magnesium chloride 0.1-5%,

- cetrimide - 0.01-1.0%,

- Aerosil - 1.0-10%,

- menthol - 0.001-3.0%,

- TREN-20 - 0.001-2%,

- methylene blue - 0.01-1%,

- ethanol - 0.01-5%,

- polyvinylpyrrolidone - 10-50%,

- sorbitol - 5-30%,

- phosphoric acid - 3-15%,

- calcium chloride - 0.1-3%,

- cyanocobalamin - 0.01-1%,

- ergocalciferol - 0.5-2%.

For practical use, the following drugs developed by Raduga-R LLC have been developed and are used in medical practice: Radogel AMK - a prophylactic gel with aminoxylates, PPA-5 Rad - a bandage film with amino acids, rinses, consisting of the above components.

The use of these medicinal substances is carried out in the form of applications, rinses, protective gels. At the same time, it is recommended that under the age of 16 years, prophylaxis be carried out for 30 days at least 3 courses per year, preferably at night. After 16 years, it is enough to conduct 2 courses for 30 days. The use of these complexes after tooth whitening procedures, orthodontic treatment using braces to restore microbalance in enamel tunnels is especially shown.

Radogel-AMK has shown its high efficiency in normalizing the metabolic processes of tooth hard tissues under the development of the carious process, has a remineralizing ability and restores the lack of arginine, lysine and histidine in enamel tunnels.

Acts of introducing into practice the dental institutions of the Russian Federation of Voronezh, Belgorod, Lipetsk, Kursk, Tambov confirm the high efficiency of the proposed gel.

Information sources

1. US patent No. 5015628. Anticariogenic phosphopeptides, dated May 14, 1991, MKI C07K 7/08; A61K 39/12, A61K 39/42, G01N 33/53.

2. Application of the Russian Federation No. 2003101428. Local action for the prevention and treatment of caries, dated July 27, 2004, IPC ⁷ A61K 6/02, A61K 9/70, A61K 31/66.

3. US patent No. 6780844. Calcium phosphopeptide complex, dated August 24, 2004, IPC ⁷ A61K 38/03, A61K 07/16.

4. Leontiev V.K., Kunin A.A., Popova T.A., Ippolitov Yu.A. Features and carious microstructures of tooth enamel, sb. Scientific works of VGMA, Voronezh, 2002: 59-62.

5. Kunin A.A. Morphological features of diseases of hard tissues of teeth, periodontal and oral mucosa: past, present and future, “Maestro of Dentistry”, No. 1-2 (14), 2004: 40-48.

Claims (21)

1. Therapeutic and prophylactic agent for tooth enamel, characterized in that it contains histidine 0.001-1.0%, lysine 0.01-2.0%, arginine 0.1-5.0%, each of these amino acids of the total weight and distilled water 20-90% of the total mass. 2. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 0.5-10% sodium carboxymethyl cellulose. 3. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 0.5-40% glycerin. 4. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains potassium chloride of 0.1-10%. 5. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains calcium glycerophosphate 0.1-5%. 6. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains calcium gluconate 0.5-10%. 7. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 0.1-3% calcium orthophosphate. 8. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises a zeolite of 0.1-3%. 9. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains magnesium chloride 0.1-5%. 10. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains cetrimide 0.01-1.0%. 11. Therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains Aerosil 1.0-10%. 12. Therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises menthol 0.001-3.0%. 13. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains TREN-20 0.001-2%. 14. Therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises methylene blue 0.01-1%. 15. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 0.01-5% ethanol. 16. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 10-50% polyvinylpyrrolidone. 17. Therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it contains sorbitol 5-30%. 18. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises 3-15% phosphoric acid. 19. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains calcium chloride 0.1-3%. 20. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it further comprises cyanocobalamin 0.01-1%. 21. The therapeutic and prophylactic agent for tooth enamel according to claim 1, characterized in that it additionally contains ergocalciferol 0.5-2%.

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