RU2238078C1 - Therapeutic and prophylactic topical-destination facility in the form of self-sticking film for remineralization of solid dental tissues - Google Patents

Abstract

FIELD: stomatology.

SUBSTANCE: invention relates to facility appropriate to prevent and to treat caries and hyperesthesia as well as remineralization of solid dental tissues. Facility is made in the form of biocompatible polymer film composed of hydrophilic and hydrophobic layers, the former including fluoride ions, calcium compounds, and phosphorus-containing compounds as well as antimicrobial and auxiliary substances.

EFFECT: achieved strictly controlled and simultaneous supply of calcium, phosphate, and fluoride ions.

14 cl, 6 ex

Description

The invention relates to medicine, in particular dentistry, and describes a local action for remineralization of hard tissues of the tooth. Local action agents are known, such as varnishes, gels, creams, sealants, solutions containing fluorine-containing compounds for the prevention and treatment of caries (Handbook of Dentistry, 1993, Moscow: Medicine, p. 484; L.N. Maksimovskaya, P.I. Roshchina, Medicines in Dentistry, Directory, Moscow: Moscow, 2000).

One of the most successful local remedies for the prevention and treatment of dental caries is bilayer hydrophilic-hydrophobic films of local action containing sodium fluoride and chlorhexidine bigluconate. Preparations are included in the hydrophilic adhesive layer of the film. The film with the hydrophilic side is tightly fixed on the surface of the teeth and gums, is held for several hours and ensures the receipt of a strictly controlled amount of fluoride ions in the affected area (Pat. RF No. 2179454). The combination of fluorotherapy with an antibacterial effect due to the presence of chlorhexidine bigluconate gives the film a combined effect and high efficiency. However, the use of only fluorine-containing topical agents for the prevention and treatment of caries is insufficient.

1. Local application of fluoride preparations, enamel treatment with fluoride salts in varnishes and gels does not sufficiently stimulate remineralization - only surface layers are remineralized. (A.Knappvost Dentistry for All, 2001, No. 3, p. 38-42).

2. Long-term observations in organized children's groups showed that for the prevention of caries, in addition to the use of local fluoride preparations, it is also advisable to use calcium preparations inside (VN Kalashnikov. Dentistry for all, 2001, No. 3, p. 23-25).

3. It was found that the remineralizing properties of saliva are enhanced in the presence of calcium salts (especially godophosphate and lactate) (T. Yanagisawa et al. Bull Tokyo dent Coll, 2001, vol. 42, No. 2, pp. 108-109). Rinsing the mouth with calcium lactate solution helps prevent enamel demineralization by 25-55% (Kashket S., Yaskell T., Arch. Oral., Biol, 1992, 37 (3), p. 187-191).

Developed calcium-containing compounds (the so-called synthetic saliva, consisting of CaCl ₂ · H ₂ O, NaCl, KCl, KH ₂ PO ₄ and Na ₂ HPO ₄ · 2H ₂ O at pH 5) for remineralization of hard tooth tissues (US Pat. US 5,279,814) .

4. The use of chewing gums with calcium compounds (dicalcium phosphate, monocalcium phosphate monohydrate, tetracalcium phosphate with dicalcium phosphate anhydride, α-tricalcium phosphate) increases the salinizing properties of saliva, creates an additional reserve of calcium and phosphate ions in the dental plaque, which has a beneficial effect on the nature of mineral metabolism (Chow LC et al. J. Dent. Res, 1994.73 (1); p. 26-32; Vogel GL et al. J. Dent. Res, 2000, 79 (1); p. 58-62).

5. For the prevention of dental caries and remineralization of the teeth, gels, solutions, films containing amorphous calcium compounds such as calcium phosphate, calcium phosphate fluoride, calcium carbonate calcium phosphate are proposed (US Pat. No. 5,037,639; 5460803; 5437857; 5502895).

Thus, it has been unequivocally proved that calcium salts, especially in combination with phosphate groups, have a pronounced ability to prevent enamel demineralization. This effect is further enhanced if the combined effect of calcium and phosphate-containing compounds with fluorine-containing compounds occurs.

6. It is well known that among the factors contributing to tooth decay, a high degree of microbial contamination of the oral cavity occupies a leading position (Silverstone L.M. Dent Update 10, 261-273, 1983). This primarily refers to bacteria of the Streptococcus mutans type in the oral cavity. Reducing their number on the surface of the teeth is one of the effective ways to prevent the development of caries (for example, I. Osfela and J. Tenovuo, Scand J. Dent. Rev., 98.1 1990). Thus, analysis of existing material shows that the means for the prevention and treatment of caries and hyperesthesia of hard tissues of the tooth:

1. Must be performed in such a local dosage form to ensure the receipt of a strictly controlled amount of calcium, phosphate and fluorine compounds on the surface of the tooth.

2. Must prevent the spread of the components of the remineralizing mixture throughout the oral cavity, to prevent their uncontrolled exposure to the teeth and the ingress of these compounds, especially fluoride ions, into the gastrointestinal tract.

3. In addition to remineralizing activity, they must also have an antimicrobial effect.

The technical task of this invention is to expand the arsenal of local drugs, in particular the creation of funds for the simultaneous delivery of a strictly controlled amount of calcium compounds, phosphate and fluorion in the affected area. The tool is intended for use in dentistry for the remineralization of hard tooth tissues.

The closest in technical essence and the achieved result is a technical solution for the composition of local action for the delivery of strictly dosed quantities of fluoride ions for the prevention and treatment of dental caries, the treatment of hyperesthesia of the teeth. The composition is made in the form of a film of combined hydrophobic and hydrophilic layers. The film includes a source of fluorion, an antibacterial component and excipients (US Pat. RF No. 2179454).

They are intended for the prevention of caries and the treatment of hyperesthesia of the teeth and ensure the delivery of metered amounts of fluoride ions to the affected area. These films are produced under the name "Diplen-F" by the company "NORD-OST" (Moscow, RF) according to TU 9391-001-29244220-98 and are widely used in dental practice.

To expand the scope and create new prolonged dosage forms of local action, calcium compounds and phosphorus-containing compounds are additionally introduced into the composition of this film. Thus, calcium ions, phosphate ions, fluorions and an antibacterial agent are combined in one film.

The product is intended for local action and is used to deliver strictly dosed amounts of Ca ²⁺ PO $\genfrac{}{}{0ex}{}{\text{3-}}{\text{4}}$ and F ^- ions to the affected area. It is made in the form of a film consisting of a combined hydrophilic and hydrophobic layers. Sources of calcium, phosphate and fluoride ions are included in the hydrophilic, adhesive film layer. In some cases, to obtain a synergistic effect, a combination of two fluorine ions containing inorganic salts or a combination of inorganic and organic fluorine-containing substances was used. Antibacterial drugs are also included in the hydrophilic layer of the film. The film additionally contains a number of auxiliary components, which are included in both the hydrophilic and hydrophobic layers.

Each of these components plays a role.

The new tool has a combined effect - remineralizing, due to the presence of a combination of calcium, phosphate and fluoride ions and antibacterial, due to the presence of antimicrobial agents. In cases where the calcium compound contains phosphoric acid residues, for example, calcium phosphates, hydrophosphates, separately phosphate-containing compounds are not included in the film. Thus, the main active principle of new drugs are:

a) remineralizing components

b) hydrophilic layer of the film

c) hydrophobic film layer

g) antibacterial drugs

e) auxiliary components

1. The remineralizing components include:

A) fluorine-containing components;

B) calcium-containing components;

B) phosphate-containing components.

Sometimes fluorine and potassium-containing components are used in the form of phosphates, for example, sodium monofluorophosphate, aluminum mono- and difluorophosphates, or calcium phosphate; in these cases, a phosphate-containing component is not administered. There are cases when all of the listed ions are part of the same compound, for example, calcium phosphate fluoride, amorphous calcium carbonate phosphate fluoride, etc.

A) Inorganic and complex fluorine-containing compounds, mixtures of two or more metal fluorides, mixtures of organic and inorganic fluorine-containing compounds were used as sources of fluoride ions in the films.

a) Inorganic water-soluble fluorides of the type MF, MF ₂ , MF ₃ , MF ₄ , their complex compounds, such as sodium fluoride, potassium fluoride, aluminum fluoride, lithium fluoride, cesium fluoride, ammonium fluoride, copper fluoride, tin fluoride, iron fluoride, nickel fluoride, palladium fluoride, silver fluoride, zinc fluoride, zirconium fluoride, indium monofluorophosphate, tin chlorofluoride, calcium fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, mono-aluminum phosphate, phosphorium phosphate, fluorine zirconium phosphate, difluorophosphate, .

b) Mixtures of inorganic fluorides of the MF _x type with MF _y , such as sodium fluoride with tin fluoride, ammonium fluoride with tin fluoride, copper fluoride with calcium fluoride, sodium fluoride with indium fluoride.

c) Organic fluorine-containing compounds: fluorides of quaternary ammonium compounds of various structures of the N ⁺ F ^{- type} , quaternary ammonium compounds with perfluoroalkyl groups, polycationic polymers containing fluorions.

Water-soluble amine hydrofluorides of the type R-NH ₂ · HF (US Pat. US 3,175,951; 3,083,143; 3,914,406):

- fluorophosphates, fluorooctanates of ammonium compounds

- water soluble amino acid complexes with metal fluorides

- mixtures of inorganic and organic fluorides, tin fluoride with benzalkonium fluoride, laurylamine hydrofluoride with tin fluoride, betaine hydrofluoride with sodium fluoride.

B) As a calcium-containing component, the composition of the film included:

a) calcium compounds not containing phosphate residues: calcium nitrate, calcium chloride;

b) calcium compounds also containing phosphate residues: calcium hydrogen phosphate, dicalcium phosphate, α-tricalcium phosphate, amorphous calcium carbonate phosphate, hydroxyapatite.

C) Calcium compounds simultaneously containing Ca ²⁺ PO $\genfrac{}{}{0ex}{}{\text{3-}}{\text{4}}$ and F ^are ions such as amorphous calcium phosphate fluoride, amorphous calcium carbonate phosphate fluoride.

2. The main component for the hydrophilic layer was water-soluble natural or synthetic polymers and copolymers and their derivatives, in particular polysaccharides or their derivatives, such as tragacanth (gelatin table), denatured gelatin and collagen treated with succinic acid or phthalic anhydride, starch and its esters, cellulose ethers such as carboxymethyl cellulose, hydroethyl cellulose, methyl hydroxypropyl cellulose, guar, acaciagum, gum arabic, agarose, agar agar, xanthan gum, carob bean flour, pectins, floor alginic acid and measures its salts (sodium and ammonium), propylene glycol alginate, chitin, chitosan, and their salts (sodium and ammonium); synthetic polymers and copolymers such as polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycols, copolymers based on vinyl acetate, vinylpyrrolidone, vinyl esters of maleic acid, polymers of acrylic and methacrylic acids, their salts and ethers, water-soluble polymers of lactic and glycolic polymers, water and water polyurethanes acids with polysaccharides and their derivatives (acetates, alkyl-, hydroxypropyl-carboxymethyl celluloses, starches, amyloses, etc.), polyvinyl alcohol and its production bubbled.

3. The main component for the hydrophobic layer (substrate) was water-insoluble or sparingly soluble polymers such as ethyl cellulose, propyl cellulose, cellulose acetate, carboxymethyl cellulose, collagen, polymers of acrylic esters, polyvinyl alcohol derivatives, polyurethanes treated with F-gas, polyolefins crosslinked derivatives of alginic acid, nonwoven materials, sparingly soluble modifications of biodegradable polymers, polyglycolic acid, polylactic acid, polytetramethylglycomide, polik prolaktona, poly (DL-dekanollaktona) polialkilenadipinaty and their copolymers, some ionoobmnennye resin.

4. Antimicrobial agents - benzalkonium chloride, benzethonium chloride, methylbenzetonium chloride, cetylpyridinium chloride, cetrimide, chlorhexidine salts, polyvinylpyrrolidone-iodine, imidazolidinylurea, diazolidinyl-urea, hydrogen sulfide, hydroxymethylamine, and others. , Ag proteins, dioxidine, phenol and its derivatives, other antibacterial drugs. Antibiotics of the penicillin group, cephalsparins, aminoglycosides, tetracycline, macrolides, lincosamides, peptide antibiotics, antimicrobial agents of various groups, herbal remedies with antimicrobial activity, etc.

5. Auxiliary components

a) plasticizers - the content of plasticizers in both the hydrophilic and hydrophobic layers should not exceed 10% of the weight of the main polymer component of this layer;

b) components prolonging the action of drugs are used in an amount of from 0.005 to 0.05 mg / cm ² in the finished film;

C) pH-regulating components are used in an amount of from 0.05 to 0.5 mg / cm ² in the finished film;

d) crosslinking agents — used for crosslinking a hydrophobic layer with a hydrophilic one — they are used in an amount up to 10% of the total polymer weight.

The thickness of the films is adjustable between 0.02-0.06 mm; the ratio of the thickness of the hydrophilic layer and hydrophobic is from 1:10 to 10: 1.

Films were obtained in two stages: first one of the layers (preferably hydrophobic) was cast on a horizontal surface, then a second layer was cast on a dried surface.

The following describes the receipt of films.

1. Preparation of stock solutions

a) for casting a hydrophobic layer:

40 g of a polymer intended for casting a hydrophobic layer, and 5 g of a plasticizer are dissolved in 500 cm ^{3 of} isopropyl alcohol (s.h. brand) with stirring and when heated in a water bath at 40-45 ° C. The resulting solution is cooled to 25 ° C and filtered through nylon fabric for screens No. 49-67 (GOST 1748-82);

b) for casting a hydrophilic layer:

to 830 cm ^{3 of} deionized water, 120 g of polymer intended for casting a hydrophilic layer, 13.4 g of plasticizer are added with stirring. Dissolution is carried out at a temperature of 40-45 ° C for 6 hours; if necessary, mixing can be carried out for another 2 hours at 80-85 ° C. Cool the solution to 25 ° C, filter through a nylon cloth.

2. Film casting

a) applying a hydrophobic layer:

20 cm ^{3 of the} prepared solution for casting the hydrophobic layer is applied to the horizontal surface of polished glass with a release coating of 30 × 40 cm in size, the solution is evenly distributed with a glass rod. Drying is carried out in a chamber in an inert gas stream at a temperature not exceeding 30 ° C for 5 hours;

b) casting a hydrophilic layer:

60-70 cm ^{3 of the} solution is applied to the dried surface of the hydrophobic layer described above to obtain a hydrophilic layer: the solution is evenly distributed on the surface and dried at a temperature of no higher than 25 ° C in an inert gas stream for about 48 hours. The end of the drying is controlled by the water content in the finished film; it should be in the range of 5-7%, but not higher than 10%.

c) The calculated amounts of remineralizing components and auxiliary substances are introduced into the solutions of the hydrophilic and / or hydrophobic layers before their application.

The following are specific formulations for preparing films.

Example 1

To 70 cm ^{3 of the} solution for applying the hydrophilic layer, the calculated amounts of auxiliary components are added, stirred at 25 ° C until complete dissolution. Then 10 ml of a 2% solution of chlorhexidine bigluconate and 10 ml of a 2% solution of sodium fluoride are introduced and mixed again until dissolved. In the resulting solution is suspended 0.2 g of calcium hydrogen phosphate obtained by the method described in Pat. USA 3635860. The resulting mixture is applied to the surface of a pre-prepared dried hydrophobic layer measuring 30 × 40 cm, uniformly distributed over the surface and dried in an inert gas stream at 25-35 ° C to a moisture content of 5-7%. The finished two-layer film is picked up with a knife, carefully pulled it off the glass and cut into a size of 50 × 100 mm; the content of chlorhexidine and sodium fluoride ranges from 0.01-0.03 mg / cm ² .

The film additionally contains a prolonging component in an amount of 0.005 to 0.05 mg / cm ² , a pH-regulating component in an amount of 0.05 to 0.5 mg / cm ² , a crosslinking agent in an amount of up to 5% by weight of the finished film. The film thickness is adjustable 0.02-0.06 mm; the ratio of the hydrophilic layer to the hydrophobic is 10: 1 (preferably 5-7: 1).

Example 2

Analogously to example 1, a film is prepared in which Catamine AB (alkyldimethylbenzylammonium chloride, benzalkonium chloride) is introduced as an antibacterial component. The content of the components of the remineralizing mixture and benzalkonium chloride in the finished film ranges from 0.01 mg / cm ² , the thickness is 0.02-0.06 mm; the content of auxiliary components is not more than 20% by weight of the film.

Example 3

Analogously to example 1, a film is prepared with sodium fluoride, chlorhexidine, in which anhydrous dicalcium phosphate obtained according to US patent 4721615 is introduced as a calcium-containing component. The content of the components of the remineralizing mixture and chlorhexidine in the finished film is not less than 0.015 mg / cm ² at a film thickness of 0 , 04-0.06 mm; the content of auxiliary components does not exceed 20% by weight of the film.

Example 4

To 70 cm ^{3 of the} solution for applying the hydrophilic layer is added the calculated amount of auxiliary components. Stirred at 25 ° C until completely dissolved. Then, 10 cm ^{3 of a} 2% solution of chlorhexidine bigluconate is added, 0.2 g of calcium carbonate phosphate fluoride obtained by the procedure described in Pat. USA 5460803. Further, the film is cast analogously to example 1. The content of chlorhexidine and components of the remineralizing mixture in the finished film is 0.01-0.03 mg / cm ² .

Example 5

Analogously to example 4, a film is prepared with a mixture of calcium salts - amorphous calcium phosphate, calcium phosphate fluoride and calcium carbonate phosphate, obtained by the method described in Pat. U.S. 5460803.

The content of chlorhexidine bigluconate and the components of the remineralizing mixture in the finished film leaves 0.01-0.03 mg / cm ² .

Example 6

The calculated amount of auxiliary components is added to 30 cm ^{3 of the} solution for applying the hydrophilic layer, stirred at 25 ° C until completely dissolved, 5 cm ^{3 of a} 2% solution of cetyl pyridinium chloride are added, mixed and subsequently suspended are 3 mM calcium chloride, 2 mM sodium phosphate and 0 5 mM sodium fluoride. In the finished film, a partial formation of a mixture of amorphous calcium phosphate, calcium fluorophosphate occurs. A similar mixture of amorphous compounds is formed upon contact of the same components (in the form of a paste, gel, etc.) with saliva (US Pat. US 5037639). The content of cetylpyridinium chloride and components of the remineralizing mixture in the finished film leaves 0.01-0.03 mg / cm ² .

Claims (14)

1. Local action, for the prevention and treatment of caries, tooth hypersthesia in the form of a biocompatible polymer film made of hydrophobic and hydrophilic layers, including a fluorion source, antimicrobial component and excipients, 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. 2. The tool according to claim 1, characterized in that inorganic and complex fluorine-containing compounds of a mixture of two or more metal fluorides, a mixture of organic and inorganic fluorine-containing compounds are used as a source of fluorions. 3. The tool according to claim 1, characterized in that the source of fluoride ions contains inorganic water-soluble fluorides of the type MF ₁ , MF ₂ , MF ₃ , MF ₄ , their complex compounds selected from the group of sodium fluoride, potassium fluoride, ammonium fluoride, tin fluoride, aluminum fluoride, copper fluoride, calcium fluoride, sodium fluorosilicate, ammonium fluorosilicate, lithium fluoride, cesium fluoride, iron fluoride, nickel fluoride, palladium fluoride, silver fluoride, zinc fluoride, zirconium fluoride, sodium monofluorophosphate , barium fluoride, n fluorozirconate Tria, mono- and diftorfosfat alumina, fluorinated sodium calcium pyrophosphate. 4. The tool according to claim 2, characterized in that the source of fluoride ions contains mixtures of inorganic fluorides of the type MFx, MFy selected from the group of sodium fluoride with tin fluoride, ammonium fluoride with tin fluoride, copper fluoride with calcium fluoride, sodium fluoride with indium fluoride. 5. The tool according to claim 2, characterized in that as the sources of fluorine ions it contains organic fluorine-containing compounds - fluorides of quaternary ammonium compounds of type N $\genfrac{}{}{0ex}{}{\text{+}}{\text{4}}$ F ^- , quaternary ammonium compounds with perfluoroalkyl groups, polycationic polymers containing fluorions; fluorophosphates, fluorooctanates of ammonium compounds; water-soluble complexes of amino acids with metal fluorides. 6. The tool according to claim 2, characterized in that it contains mixtures of inorganic and organic fluorides selected from the group of tin fluoride with benzalkonium fluoride, laurylamine hydrofluoride with sodium fluoride, betaine hydrofluoride with sodium fluoride as a source of fluoride ions. 7. A compound according to claim 1, characterized in that an antimicrobial component it contains substances selected from the group of benzalkonium chloride, benzethonium chloride, methylbenzethonium chloride, cetylpyridinium chloride, tsetrimil, chlorhexidine salts, polyvinylpyrrolidone-iodine, imidazolidinyl urea, diazolidinyl urea, hydrogen peroxide and its crystal complexes with urea, or polyvinylpyrrolidone, or cyclodextrin, Ag-sulfisine, Ag-proteins, phenol and its derivatives, antibiotics of the penicillin group, cephalosporins, tetracycline, macrolides, lincosamides, peptide antibiotics, phytopreparations antimicrobial action. 8. The tool according to claim 1, characterized in that it as a source of calcium contains compounds selected from the group of calcium compounds that do not contain phosphate residues, calcium nitrate, calcium fluoride, calcium compounds containing phosphate residues, calcium hydrogen phosphate, dicalcium phosphate, a-tricalcium phosphate, amorphous calcium carbonate phosphate. 9. The tool according to claim 1, characterized in that it includes calcium compounds simultaneously containing PO $\genfrac{}{}{0ex}{}{\text{3-}}{\text{4}}$ and F ^- ions, such as amorphous calcium phosphate fluoride, amorphous calcium carbonate phosphate fluoride. 10. The tool according to any one of claims 1 to 9, characterized in that it contains a plasticizer as auxiliary substances, while it can be included in both the hydrophilic and hydrophobic layers in an amount of not more than 10% by weight of the main polymer component of the layer . 11. The tool according to any one of claims 1 to 9, characterized in that, as auxiliary substances, it contains substances that prolong the action of drugs in an amount of from 0.005 to 0.05 mg / cm ² film. 12. The tool according to any one of claims 1 to 9, characterized in that as auxiliary substances it contains pH regulatory components in an amount of from 0.05 to 0.5 mg / cm ² film. 13. The tool according to any one of claims 1 to 9, characterized in that it contains crosslinking agents for the hydrophilic and hydrophobic layers in an amount of 10% of the total polymer weight. 14. The tool according to any one of claims 1 to 13, characterized in that the film thickness is from 0.02 to 0.06 mm with a ratio of hydrophilic and hydrophobic layers of 1: 10-10: 1.