RU2535045C1 - Tooth paste containing regeneration stimulators - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: formulation of initial ingredients of the presented tooth paste for treating and preventing dento-facial inflammatory diseases involves a tissue regeneration stimulator specified in hyaluronic acid or sucralfate, or ε-acetylaminocapronic acid sodium salt, the enzymes lysozyme, papaine and hyaluronidase, as well as an abrasive ingredient, a moistening agent, hydrocolloid, a surfactant, sodium fluoride, tetrapotassium pyrophosphate, a preserving agent, a flavouring agent and water in certain amounts.

EFFECT: effective oral cleaning and removal of plaque, reduced bleeding gum and oral inflammations, faster dento-facial regeneration in the inflammations.

4 cl, 9 tbl, 3 ex

Description

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

The present invention relates to medicine, namely to dentistry. To increase the cleaning, antimicrobial, anti-inflammatory and regenerative effects, a toothpaste has been developed, the composition of the initial components of which includes: enzymes: papain, lysozyme, hyaluronidase and tissue regeneration stimulants: hyaluronic acid or sucralfate, or the sodium salt of ε-acetylaminocaproic acid. The proposed toothpaste can reduce inflammation and accelerate the regeneration processes in the tissues of the dentition in inflammatory diseases. Toothpaste has good organoleptic properties: it is white in color, with a pleasant smell and good taste.

 State of the art

Compositions for the oral cavity, such as toothpastes, gels, elixirs, balms, rinses, are mainly intended to remove plaque and / or prevent its formation with regular use. Dental plaque is a multi-component, constantly forming biotope of the oral cavity, the basis of which is almost all representatives of the microflora of the oral cavity in a conglomerate with proteins and polysaccharides. In the process of plaque formation, a marked change in the composition of microflora occurs. In the first phase, lasting 2-4 hours, an early plaque is formed with a predominance of aerobic and facultative anaerobic bacteria - streptococci, staphylococci, neisseria and lactobacillus. The total bacterial content is not more than 100-1000 in 1 g. In the second phase (day 4-5), aerobic and facultative anaerobic microflora shift towards anaerobic leptotrichia and fusobacteria. The total bacterial content increases to 1-10 million in 1 g. In the third phase (days 6-7 and further), the formation of a qualitative composition of dental plaque ends - the content of aerobes and facultative anaerobes sharply decreases and obligate anaerobes (bacteroids, fusobacteria, veilonella prevail) , actinomycetes, peptostreptococci), emitting a complex of toxic substances that cause the destruction of Ig A and Ig G, a sharp shift in pH to the acid side, which leads to the progression of microbial invasion, the development of caries and periodontal diseases.

In some cases, with sluggish inflammatory and dystrophic processes in the periodontium against the background of a decrease in the immunological reactivity of the body and nonspecific protection factors, it is advisable to use stimulants that can be included in the composition of toothpastes.

A set of therapeutic and preventive measures using toothpastes containing tissue regeneration stimulants should be carried out during the period of remission, after the elimination of acute inflammatory phenomena.

The known drug Acemine containing the sodium salt of ε-acetylaminocaproic acid. A feature of the action of Acemine is to reduce exudation, accelerate the cleansing of the wound from purulent necrotic masses, as well as epithelization and tissue regeneration. (Mashkovsky M.D. Medicines. - 15th ed., - M.: New Wave, 2006. - p. 715).

Known drug Sucralfate containing the basic aluminum salt of sucrose octasulfate. The drug has an antacid, adsorbing, enveloping and cytoprotective effect. (Mashkovsky M.D. Medicines. - 15th ed. - M.: New Wave, 2006. - p. 323).

Known drug Gialgan Phidia, used as a stimulant of reparative processes and representing a sterile, pyrogen-free, viscous buffer aqueous solution of a fraction of high purity sodium salt of hyaluronic acid with a molecular weight of from 500 to 730 kD. Hyaluronic acid - an essential component of the extracellular matrix, is present in high concentrations in the composition of articular cartilage and synovial fluid. Endogenous hyaluronic acid provides the viscosity and elasticity of the synovial fluid, and it is also necessary for the formation of proteoglycans in the articular cartilage. With osteoarthritis, deficiency and qualitative changes in hyaluronic acid in the composition of synovial fluid and cartilage are noted. Intra-articular administration of hyaluronic acid against the background of degenerative changes in the surface of the synovial cartilage and pathology of the synovial fluid leads to an improvement in the functional state of the joint - (http://www.wiki-meds.ru/lekarstvennie-preparati/gialgan-fidiya-552.htm).

Chitoxy-20 (polyethylene glycol ether of chitosan) is known, which is a water-soluble form of chitosan. Chitosan is a saponification product of a natural carbohydrate-containing biopolymer - chitin, which, along with cellulose, is the most common organic substance in nature. The use of chitosan in cosmetic compositions is due to its following properties:

- biocompatibility with human cells;

- regenerative effect on the skin;

- antibacterial effect;

- antifungal effect;

- ability to retain moisture.

Chitoxy-20 is a viscous transparent liquid of light yellow color, odorless, easily soluble in water at any pH. The ideal solubility in water allows the use of Hitoxy-20 as a component in any percentage. The consistency of this form of chitosan can be regulated (taking the form that is most convenient for use in this type of cosmetics). The drug Chitoxy-20 preserves all the useful properties of the initial chitosan and has new specific properties:

- pronounced hydrating properties; forms around itself a "fur coat" of water molecules, including tightly bound water;

- the ability to form semipermeable films that keep the skin hydrated by passing oxygen, i.e. allow the skin to breathe;

- the ability to stabilize other components of the composition, for example vitamins -

(http://www.akvion.ru/catalog/skk/skkhitoksi.php).

Known drug Lysozyme, available in the form of hermetically sealed vials of 0.05; 0.1 and 0.15 g, which has a bacteriolytic effect and has the ability to stimulate the nonspecific reactivity of the body. Lysozyme catalyzes the hydrolysis of 1,4 - bonds between N-acetylmuramic acid and 2-acetamido-2-deoxy-D-glucose (N-acetylglucosamine) contained in mucopolysaccharides, mucopeptides and chitin of the cell walls of bacteria, fungi and protozoa, has a pronounced antimicrobial (destroys the cell walls of most gram-positive and some gram-negative bacteria), mycostatic (inhibits the development of microscopic fungi), and wound healing effect (Found on the Internet: <URL: http: //provizor.org/node/11671).

The known drug Lidase containing the enzyme hyaluronidase is an enzyme whose specific substrate is hyaluronic acid. The latter is a mucopolysaccharide containing acetylglucosamine and glucuronic acid. Hyaluronic acid has a high viscosity; its biological significance lies mainly in the fact that it is a cementing substance of connective tissue. Hyaluronidase (the “distribution factor”) contained in various tissues of the body causes the breakdown of hyaluronic acid to glucosamine and glucuronic acid and thereby reduces its viscosity, increases the permeability of tissues and facilitates the movement of fluids in interstitial spaces. The action of hyaluronidase is reversible. With a decrease in its concentration, the viscosity of hyaluronic acid is restored. Thus, hyaluronidase can be used to temporarily reduce the viscosity of hyaluronic acid. The ratio of the system "hyaluronic acid - hyaluronidase" is largely regulated by the permeability of tissues. Lidase is used to accelerate the absorption of drugs. The therapeutic effect is manifested by softening of scars, improvement of joint mobility, elimination or reduction of contractures, resorption of hematomas. (Mashkovsky M.D. Medicines. - 15th ed. - M.: New Wave, 2006. - p. 660).

The known enzyme is papain, a plant proteolytic enzyme of the hydrolase class, exhibiting broad substrate specificity: it catalyzes the hydrolysis of peptide bonds in proteins and peptides, and also hydrolyzes amides, esters and thioethers. Freeze-dried powder "Papain" is used in medicine together with lysozyme for the treatment of intervertebral hernia, in the form of powders and lotions in dentistry for gingivitis and periodontitis, and other inflammatory conditions of the oral cavity. (Found on the Internet:

<URL: http: //slovari.yandex.ru/%D0%BF%D0%B0%D0%BF%D0%B0%D0%B8%D0%BD/%D0%91%D0%A1%D0%AD /% D0% 9F% D0% B0% D0% BF% D0% B0% D0% B8% D0% BD /).

Various therapeutic and prophylactic toothpastes used for the prevention of inflammatory periodontal diseases, containing anti-inflammatory and antimicrobial components, for example extracts of medicinal plants and vitamins (Silica Herb plus ® therapeutic and prophylactic toothpaste (Germany) and tea tree oil, are known from the prior art) paste "Natural whitening toothpaste with tea tree oil" ® (USA). However, this paste has a low cleaning ability, because it does not contain components that directionally dissolve plaque.

Known Audrey-Dent toothpaste for the elimination and prevention of various inflammatory processes in the oral cavity, containing liposomes, antiseptic - dioxidine, urea, Maclea extract, vitamins C and P. (http://liderm.audrie.ru/audrie/audrie_catalog/audrie_dentifrice /34-zubnaya-pasta-odri-dent.html).

Known toothpaste Lacalut Brilliant White Menta®, which removes plaque due to highly abrasive compounds.

Known desensitizing paste Colgate® Sensitive Pro-Relief ™ containing arginine and calcium carbonate to reduce tooth sensitivity. (http://www.colgateprofessional.ru/products/5938a27a02315210b27a0231521028016e0aRCRD/specifics).

Known toothpaste with an enzyme-containing composition, where the enzyme is selected from the group of proteinases, including papain, which destroys the protein base of plaque (Rembrandt® Whitening toothpaste (USA), as well as a paste containing lysozyme, glucose oxidase, lactoperoxidase and lactoferrin (tooth Biotene® paste (Finland), which is used to treat xerostomia The described toothpaste generates active forms of oxygen during toothbrushing and can only affect aerobic and facultative anaerobic bacteria.

From RU 2452508, a method for stimulating healing of skin wounds is known, comprising administering a Gly-His-Lys peptide, characterized by using a combination of Gly-His-Lys peptides and thymogen parenterally in equimolar single doses of 0.5 μg / kg body weight once every day, for ten days.

A toothpaste is known from RU 2407512 C1, which contains enzymes: papain, dextranase, alpha-amylase, invertase or glucoamylase, glucose oxidase, lactoperoxidase, lysozyme or lactoferrin, to restore the oral microflora and prevent inflammatory periodontal diseases.

From RU 2333768 C2, enzyme-containing compositions with cetylpyridinium chloride with improved hygienic properties against plaque are known.

Known adhesive balm for the gums Asept® containing chlorhexidine bigluconate - an antiseptic that is effective against aerobic and facultative anaerobic bacteria and metronidazole - an antibacterial component that is effective against anaerobic bacteria and protozoa.

Known gel toothpaste Dentofam® containing a concentrate of bacteriophages, selective for species Streptococccus and Staphylococcus.

Known medical and preventive toothpaste N-ZIM Prebio, manufactured by Artlife since 2009 (Medical and preventive toothpaste N-ZIM Prebio. 08/02/2011, Found on the Internet: <URL: http: //www.artlife-chel.ru / main / 466-n-zim-prebio>), includes a lactobacillus lysate, which increases local immunity, thereby preventing the propagation of pathogenic microorganisms in the oral cavity and the preservation of beneficial microflora. N-ZIM Prebio Toothpaste also contains the enzyme papain, which effectively breaks down plaque without damaging tooth enamel.

According to Artlife, N-ZIM Prebio Toothpaste contains:

demineralized water, sorbitol, silicon dioxide, dicalcium phosphate dihydrate, polyethylene glycol, sodium lauroyl sarcosinate, sodium carboxymethyl cellulose, flavoring agent, D-panthenol, sodium lauryl sulfate, lysine, titanium dioxide, papain, sodium fluoride, saccharin lactamide, laminofluoride, aminoferin propyl paraben, stevioside, aloe extract; while the mass fraction of fluoride is at least 0.1%.

Toothpaste compositions are known from RU 2355420 and RU 2381021, including enzymes, in particular lidase, lysozyme and papain, as well as tetracal pyrophosphate.

The declared toothpaste differs from RU 2355420 and RU 2381021 in that it contains tissue regeneration stimulants: hyaluronic acid or sucralfate, or the sodium salt of ε-acetylaminocaproic acid.

Compositions for the oral cavity, such as toothpastes, gels, elixirs, rinses, for the manufacture of which use enzymes: papain, lysozyme, hyaluronidase and tissue regeneration stimulants: hyaluronic acid or sucralfate or the sodium salt of ε-acetylaminocaproic acid, are not described.

Thus, the object of the present invention is to provide an oral composition, the composition of the starting components of which includes: enzymes: papain, lysozyme, hyaluronidase and tissue regeneration stimulants: hyaluronic acid or sucralfate, or the sodium salt of ε-acetylaminocaproic acid, which can be used for oral hygiene, restoration of the natural pH level, reduction of inflammatory phenomena and acceleration of the regeneration processes in the tissues of the dentition in inflammatory conditions Levania.

SUMMARY OF THE INVENTION

According to the present invention, it was unexpectedly discovered that the introduction of toothpaste as initial components: enzymes: papain, lysozyme, hyaluronidase and tissue regeneration stimulants: hyaluronic acid or sucralfate or sodium salt of ε-acetylaminocaproic acid helps to normalize the natural pH level, reduce inflammation and accelerate the regeneration processes in the tissues of the dentition in inflammatory diseases.

Description of preferred embodiments

Papain, lysozyme and hyaluronidase are introduced into the toothpaste at a concentration of from 0.001 to 5.0 wt. %, and preferably from 0.01 to 5.0 wt. %; sucralfate or sodium salt of ε-acetylaminocaproic acid in a concentration of from 0.001 to 5.0 wt. %

Enzymes that can be used in the practice of the present invention are represented by proteases, hydrolyzing proteins, hyaluronidase and lysozyme. Plant proteases can be used as proteolytic enzymes: chymopsin, ficin, papain and bromelain in a concentration of from 0.01 to 5.0 wt. % and preferably from 0.1 to 5.0 wt. %

Lysozyme derived from egg white with a molecular weight of approximately 15,000 amu has an antimicrobial effect against gram-positive bacteria and to a lesser extent gram-negative, hydrolyzing fragments of the peptidoglycan wall of bacteria, and can be used in a concentration of from 0.01 to 5.0 wt. % and preferably from 0.1 to 5.0 wt. %

Hyaluronidase can be used in a concentration of from 0.01 to 5.0 wt. % and preferably from 0.1 to 5.0 wt. %

Toothpaste

Upon receipt of toothpaste tissue regeneration stimulants:

hyaluronic acid or sucralfate, or the sodium salt of ε-acetylaminocaproic acid and enzymes are mixed with the base of the toothpaste and get a product that helps normalize the natural pH level, reduce inflammation and accelerate the regeneration processes in the tissues of the dentition in case of inflammatory diseases.

Toothpaste base

Acceptable fillers used to make the toothpaste of the present invention are represented by a hydrophilic phase consisting of water and a humectant, which can be used propylene glycol, glycerin, sorbitol 70%, PEG with a molecular weight of from 200 to 400 amu or mixtures thereof. The concentration of the humidifier is usually in the amount of from 5 to 20.88 wt. % The water present in the toothpaste will make up the remaining 100 wt. % amount, after calculating the sum of the mass.% of all components of the paste.

Of the abrasives, silica-based abrasives with an average particle size of 5 to 20 microns, for example Sorbosil AC 35; AC 39; TC 15 (Inneos Silicas), Zeodent 113: 163 (J.M. Huber) and others similar in characteristics. Other abrasives used in toothpastes are tricalcium phosphate, dicalcium phosphate dihydrate, and aluminum silicate. The concentration of abrasive is usually in the amount of from 2 to 20 wt. % and preferably from 2 to 20 wt. %

Of the thickeners, natural and synthetic hydrocolloids can be used, such as carboxymethyl cellulose and its salts, hydroxyethyl cellulose, sodium alginate, sodium carrageenate, xanthan gum under various trade names. The concentration of thickener is usually in the amount of from 0.05 to 5.0 wt. %, and preferably from 0.1 to 2.0 wt. %

Of the surfactants, various anionic, cationic and nonionic surfactants are allowed for use in oral hygiene products under various trade names. The concentration of surfactant is usually in the amount of from 0.1 to 2.0 wt. % and preferably from 0.1 to 1.0 wt. %

Of the fluorides, sodium fluoride, tin fluoride, sodium monofluorophosphate, aminofluoride with a fluoride ion concentration in the range from 0.1 to 0.15 wt. Can be used. %

Of the phosphates, sodium and / or potassium tetrapyrophosphates, disodium pyrophosphate, sodium polyphosphate with a concentration of from 0.5 to 5.0 wt.% Can be used. % and preferably from 1.0 to 5.0 wt. %

Of the antibacterial substances, methyl and propyl parabens or their salts can be used with a concentration of from 0.15 to 0.4 wt. % and preferably from 0.2 to 0.3 wt. %; chlorhexidine bigluconate in a concentration of from 0.05 to 0.2 wt. %

From flavorings can be used any allowed flavoring additives with a concentration in the range from 0.05 to 1.5 wt. % and preferably from 0.1 to 1.5 wt. %

Other components that can be incorporated into the composition of the toothpaste are desensitizers, whitening additives, dyes without significantly affecting the properties and characteristics of the toothpaste according to this invention.

Getting Toothpaste

The toothpaste according to this invention is usually made by conventional methods using solid or liquid cosmetically acceptable carriers or excipients selected from emulsifiers, dispersants, preservatives, flavorings, pH adjusters, polymer carriers and other excipients that are suitable for the preparation of compositions for topical application.

Examples

As an embodiment of the claimed invention, a toothpaste is proposed, the composition of the starting components of which includes, in mass. %: 0.001-5.0 sucralfate, 0.01-5.0 lysozyme; 0.01-5.0 papain; 0.01-5.0 hyaluronidase; 2.00-20.00 abrasive component; 5.00-20.88 humidifiers; 0.05-5.0 hydrocolloid; 0.10-2.00 surfactant (surfactant); 0.10-0.32 sodium fluoride; 0.50-5.00 tetracal pyrophosphate; 0.15-0.40 preservative; 0.05-1.50 flavoring; water - the rest.

As another embodiment of the claimed invention, a toothpaste is proposed, the composition of the starting components of which includes, in mass. %: 0.001-5.0 sodium salt of ε-acetylaminocaproic acid, 0.01-5.0 lysozyme; 0.01-5.0 papain; 0.01-5.0 hyaluronidase; 2.00-20.00 abrasive component; 5.00-20.88 humidifiers; 0.05-5.0 hydrocolloid; 0.10-2.00 surfactant (surfactant); 0.10-0.32 sodium fluoride; 0.50-5.00 tetracal pyrophosphate; 0.15-0.40 preservative; 0.05-1.50 flavoring; water - the rest.

As another embodiment of the claimed invention, a toothpaste is proposed, the composition of the starting components of which includes, in mass. %: 0.001-5.0 hyaluronic acid, 0.01-5.0 lysozyme; 0.01-5.0 papain; 0.01-5.0 hyaluronidase; 2.00-20.00 abrasive component; 5.00-20.88 humidifiers; 0.05-5.0 hydrocolloid; 0.10-2.00 surfactant (surfactant); 0.10-0.32 sodium fluoride; 0.50-5.00 tetracal pyrophosphate; 0.15-0.40 preservative; 0.05-1.50 flavoring; water - the rest.

As a preferred embodiment of the claimed invention, the toothpaste indicated above, in the following ratio of components, wt. %:

Papain 0.1-5.00 Abrasive component 2.00-20.00 Humidifier 5.00-20.00 Sucralfat 0.001-5.00 Hyaluronidase 0.1-5.00 Hydrocolloid 0.10-2.00 Surfactant 0.10-1.00 Sodium Fluoride 0.10-0.32 Lysozyme 0.1-5.00 Tetracal pyrophosphate 1.00-5.00 Preservative 0.20-0.30 Flavoring 0.10-1.50 Demineralized water rest

The active ingredients of the claimed toothpaste are: papain, lysozyme, hyaluronidase, tissue regeneration stimulants: hyaluronic acid or sucralfate or the sodium salt of ε-acetylaminocaproic acid.

Papain hydrolyzes the peptide bonds of plaque, which leads to its softening and investment removal during brushing.

Lysozyme derived from egg white with a molecular weight of approximately 15,000 amu is a factor of nonspecific immunity, has an antimicrobial effect against gram-positive bacteria and to a lesser extent gram-negative, hydrolyzing fragments of the peptidoglycan wall of bacteria.

Hyaluronidase breaks down hyaluronic acid in the composition of the toothpaste and / or improves the penetration of other active components of the paste into the tissues.

The sodium salt of ε-acetylaminocaproic acid reduces exudation, accelerates the purification of tissues from necrotic masses and their epithelization and regeneration.

Sucralfate neutralizes the acidic components of purulent-necrotic masses and decomposes into aluminum, denaturing mucus proteins and sucrose sulfate, which, when combined with the denatured protein, forms a protective film on the surface of the mucous membrane.

Thus, the integrated use of the above active components leads to the following result: modification of plaque with the formation of easily removable water-soluble compounds, activation of the immune system with the aim of antimicrobial and protection from exposure to pathogenic microorganisms, normalization of the natural pH level, acceleration of periodontal tissue regeneration. The following substances are used to prepare toothpaste: Papain, Hyaluronidase, Lysozyme, Hyaluronic acid of any viscosity and molecular weight, Sucralfate, Sodium salt of ε-acetylaminocaproic acid with a basic substance content of at least 97%.

An additional advantage of this composition is the ability to increase the content of lysozyme in saliva and oral fluid.

The proposed toothpaste reduces plaque formation by 62.96% and is completely harmless and safe for prolonged use.

The significant differences of the proposed toothpaste are as follows:

The claimed toothpaste has stability with respect to the activity of the enzymes included in its composition during long-term storage, which is achieved by immobilizing the enzymes on polymer carriers contained in the composition. As these polymeric carriers, any polymers capable of binding to enzymes to form enzyme-carrier complexes can be used. Examples of such polymeric carriers are sodium alginate (FMC) and sodium carboxymethyl cellulose (Hercules).

The activity of the declared toothpaste is due to the activity of its components papain, lysozyme, hyaluronidase, hyaluronic acid or sucralfate or the sodium salt of ε-acetylaminocaproic acid. It was found that toothpaste, the composition of the starting components of which includes, in mass. %: 0.001-5.0 hyaluronic acid or 0.001-5.00 sucralfate or 0.001-5.00 sodium salt of ε-acetylaminocaproic acid, 0.01-5.0 lysozyme; 0.01-5.0 papain; 2.00-20.00 abrasive component; 5.00-20.88 humidifiers; 0.05-5.0 hydrocolloid; 0.10-2.00% surfactant; 0.10-0.32 sodium fluoride; 0.50-5.00 tetracal pyrophosphate; 0.15-0.40 preservative; 0.05-1.50 flavoring; water - the rest is stable in relation to the activity of enzymes during its long-term storage, while the activity of these enzymes, prepared in the form of a solution, rapidly decreases. Therefore, the claimed composition can be used for the effective prevention of inflammatory periodontal diseases.

The present invention is illustrated by the following examples.

EXAMPLE 1

Toothpaste for the treatment and prevention of inflammatory diseases of the dentition, for the manufacture of which papain, lysozyme, hyaluronidase and hyaluronic acid and other cosmetically acceptable carriers or excipients are used, has the following composition:

Papain 0.01 Silica 2.00 Sorbitol 70% 10.00 Hyaluronic acid 0.001 Hyaluronidase 0.01 Sodium Alginate 0.50 Polysorbate-20 0.10 Sodium Fluoride 0.05 Lysozyme 0.01 Tetracal pyrophosphate 0.50 Preservative 0.15 Flavoring 0.05 Demineralized water rest

The specified composition is prepared according to the following method. All components except sodium alginate are successively dissolved in demineralized water, then sodium alginate is added and mixed until a gel forms. The resulting toothpaste is mixed, vacuum and homogenized.

EXAMPLE 2

Toothpaste for the treatment and prevention of inflammatory diseases of the dentition, for the manufacture of which papain, lysozyme, hyaluronidase, sucralfate and other cosmetically acceptable carriers or excipients are used, has the following composition:

Papain 5.00 Dicalcium Phosphate Dihydrate 20.00 Glycerol 20.00 Sucralfat 5.00 Hyaluronidase 5.00 Sodium CMC 5.00 PEG-40 hydrogenated castor oil 2.00 Sodium Fluoride 0.32 Lysozyme 5.00 Tetracal pyrophosphate 5.00 Preservative 0.40 Flavoring 1,50 Demineralized water rest

The specified composition is prepared according to the following method. In demineralized water, all components are sequentially dissolved, except sodium CMC and dicalcium phosphate dihydrate, then sodium CMC and dicalcium phosphate dihydrate are added, mixed until a gel forms. The resulting toothpaste is mixed, vacuum and homogenized.

EXAMPLE 3

Toothpaste for the treatment and prevention of inflammatory diseases of the dentition, for the manufacture of which papain, lysozyme, hyaluronidase, sodium salt of ε-acetylaminocaproic acid and other cosmetically acceptable carriers or excipients are used, has the following composition:

Papain 0.50 Dicalcium Phosphate Dihydrate 20.00 Glycerol 20.00 Ε-acetylaminocaproic acid sodium salt 0.50 Hyaluronidase 0.10 Sodium CMC 5.00 PEG-40 hydrogenated castor oil 2.00 Sodium Fluoride 0.32 Lysozyme 0.50 Tetracal pyrophosphate 5.00 Preservative 0.40 Flavoring 1,50 Demineralized water rest

The specified composition is prepared as in EXAMPLE 2.

Assessment of the stability of enzymes in toothpaste

Since the main disadvantage of enzymes is their instability during long-term storage of finished forms based on them during the expiration date, a comparative assessment was made of the preservation of the activity of the papain enzyme during storage in the form of a solution and as a composition for topical application.

Papain activity was determined by the following methods.

To determine the proteolytic activity of papain, a modified Kunitz method was used. Such a quantity of an enzyme is taken as one proteolytic unit, upon exposure to which casein on the substrate for 10 minutes under standard conditions, such a quantity of hydrolysis products is released that leads to an increase in optical density at a wavelength of 280 nm per unit.

The results are shown in the following table 1:

As can be seen from the table 1, the introduction of enzymes in toothpastes allows you to get stable cosmetic compositions for topical use in the prevention of inflammatory periodontal diseases. Despite the fact that upon the introduction of enzymes into the composition of such compositions, a slight loss of enzymatic activity occurs, upon further storage for 1 year, the enzymes do not change their activity due to the fixation of the labile structure of the enzyme by the carrier polymer.

The antimicrobial activity of lysozyme was determined by the method of serial dilutions. As a nutrient medium used meat-peptone broth; as test microorganisms, pure cultures: Staphylococcus aureus, Bacillus cereus, Esherichia coli, Candida albicans. A one-day culture of 1000 cells / ml was added to each tube. Cell cultures: Staphylococcus aureus, Bacillus cereus, Esherichia coli were grown in test tubes in a medium with meat and peptone broth at 37 ° C for 24 hours, and the Candida albicans culture was grown on Saburo agar medium at 24 ° C for two days. Titration was started at a concentration of 10 mg / ml (1/10 dilution). As a control, a test tube was used, into which only nutrient medium and microorganism were introduced. The concentration in the last tube with no growth was taken as the minimum inhibitory concentration. To assess the bactericidal effect of the tubes with a lack of growth, reseeding was done on plates with meat and peptone broth. The cups were thermostated at 37 ° C for a day. Bactericidal action was noted in the absence of growth on a solid nutrient medium (see table 2).

As can be seen from table 2, the optimal inhibitory concentration is: for lysozyme: 2 mg / ml in the case of Staphylococcus aureus, Bacillus cereus, Escherichia coli; 30 mg / ml for Candida albicans; bactericidal concentration for lysozyme - 4 mg / ml - in the case of Staphylococcus aureus, Bacillus cereus; 40 mg / ml for Escherichia coli; 50 mg / ml - for Candida albicans.

Clinical trials of the proposed toothpaste were carried out for one month on 30 volunteers aged 21-24 years old, clinically healthy, without deformation of the teeth and jaws. To determine the cleaning effect of the paste, controlled and uncontrolled brushing of the teeth by the proposed paste was carried out. The controlled brushing of the teeth was carried out according to the method proposed in the “Methodological guidelines for experimental (pharmacological) and clinical trials of preventive and therapeutic toothpastes” (Moscow-Sofia, 1983), for 3 minutes on the 1st, 7th, 14th th, 21st and 28th day. On the remaining days, probants brushed their teeth with the same brush and paste, morning and evening, at home without control. Before and after controlled cleaning, a Green-Vermillion hygiene index was determined:

Quantitative assessment was carried out according to a 4-point system:

- staining of the entire surface of the tooth crown was evaluated at 3 points;

- staining 2/3 of the surface of the tooth crown was evaluated at 2 points;

- staining 1/3 of the surface of the tooth crown was evaluated at 1 point;

- the absence of staining of the surfaces of the teeth was evaluated at 0 points.

The calculation of the hygiene index indicators according to Green-Vermillion was carried out according to the formula:

K _cf = K / n,

where K _cf - the averaged digital index of the hygiene index for all teeth in which the index was determined;

K is the total sum of the index values for all teeth in which indicators were evaluated;

n is the number of teeth that were evaluated.

The cleaning effectiveness of toothpaste was calculated by the formula:

Purifying efficiency = [(IG _do1 -IG _DOX) / IG _do1] × 100 where

IG _do1 - an indicator of the hygiene index obtained during the initial examination, before brushing your teeth;

IG _doX - an indicator of the hygiene index obtained during a subsequent examination (7th, 14th, 21st, 28th days of the examination), before brushing your teeth.

Plaque reduction during a single brushing was determined by the formula for each controlled brushing:

Reduction = [(IG _doX- IG _afterX ) / IG _doX ] × 100, where

IG _doX - an indicator of the hygiene index obtained during examination before the start of controlled brushing (1st, 7th, 14th, 21st, 28th days);

IG _afterX is an indicator of the hygiene index obtained during examination after conducting controlled brushing of teeth (1st, 7th, 14th, 21st, 28th days).

From tables 3, 4 and 5 it can be seen that the proposed toothpaste has an increased cleaning ability, and therefore an anti-caries effect due to a more pronounced removal of dental plaque and provides the removal of 62.96% of plaque.

To determine the anti-inflammatory properties of the proposed toothpaste, all the probants (the same 30 people) carried out controlled brushing for one month.

The anti-inflammatory effect of the paste was evaluated by changing the state of the gums attached to the teeth using the PMA index according to the formula:

PMA index = [Sum of indicators / (3 × number of teeth)] × 100,

where P is the inflammation of the gingival papilla, which is estimated at 1 point;

M - inflammation of the gingival margin, which is estimated at 2 points;

A - inflammation of the attached gum of the alveolar process, which is estimated at 3 points.

Evaluation of the anti-inflammatory effect of toothpaste was carried out on the basis of an analysis of the dynamics of the PMA index, which was determined during repeated examinations on the 1st, 7th, 14th, 21st and 28th days.

Anti-inflammatory efficacy was calculated by the formula:

Anti-inflammatory efficacy = [(RMA _{1 —} RMA _x ) / RMA ₁ ] × 100,

where RMA ₁ is an indicator of the RMA index obtained during the initial examination on the 1st day of the study;

РМА _x - indicator of the РМА index, obtained during the subsequent examination (7th, 14th, 21st and 28th days).

The data are shown in Tables 6 and 7. It is clearly seen from them that after using this paste, the condition of periodontal tissues improved significantly: 100% of the probants disappeared from catarrhal gingivitis, and the PMA index decreased from 48.1 to 6.2, which corresponded to 87, 10% anti-inflammatory effectiveness of this paste.

Assessment of hemostatic effect was carried out according to the index of hemorrhage Kechke:

I degree - rarely, estimated at 2 points;

II degree - during brushing, estimated at 4 points;

III degree - with meals and spontaneously, is estimated at 8 points.

Hemostatic effectiveness was determined by the formula:

Hemostatic efficacy = [(IR _{1 —} IR _x ) / IR ₁ ] × 100,

where IR ₁ is the bleeding index at the beginning of the study;

IR _x is the bleeding index at the end of the experiment.

The data are shown in tables 8 and 9. It can be seen from them that after using this paste, the condition of periodontal tissues improves and bleeding of the gums decreases from 2.7 to 0.5 points, which corresponds to 81.48% of the hemostatic effectiveness of this paste.

Thus, the proposed toothpaste has a higher cleansing (62.96% cleansing effectiveness), anti-inflammatory (87.10% anti-inflammatory effect) and hemostatic (81.48% hemostatic effectiveness) effect.

Claims (4)

1. Toothpaste for the treatment and prevention of inflammatory diseases of the dentition, the composition of the starting components of which includes, mass. %: 0.001-5.0 hyaluronic acid or 0.001-5.0 sucralfate or 0.001-5.0 sodium salt of ε-acetylaminocaproic acid, 0.01-5.0 lysozyme; 0.01-5.0 papain; 0.01-5.0 hyaluronidase; 2.00-20.00 abrasive component; 5.00-20.88 humidifiers; 0.05-5.0 hydrocolloid; 0.10-2.00 surfactant (surfactant); 0.10-0.32 sodium fluoride; 0.50-5.00 tetracal pyrophosphate; 0.15-0.40 preservative; 0.05-1.50 flavoring; water - the rest. 2. Toothpaste under item 1, characterized in that for its manufacture using the following components, mass. %:
Papain 0.01-5.00 Abrasive component 2.00-20.00 Humidifier 5.00-20.88 Sucralfat 0.001-5.00 Hydrocolloid 0.10-2.00 Surfactant 0.10-1.00 Hyaluronidase 0.01-5.00 Sodium Fluoride 0.10-0.32 Lysozyme 0.01-5.00 Tetracal pyrophosphate 1.00-5.00 Preservative 0.20-0.30 Flavoring 0.10-1.50 Demineralized water rest 3. Toothpaste under item 1, characterized in that for its manufacture using the following components, mass. %:
Papain 0.01-5.00 Abrasive component 2.00-20.00 Humidifier 5.00-20.88 Hyaluronic acid 0.001-5.00 Hydrocolloid 0.10-2.00 Surfactant 0.10-1.00 Hyaluronidase 0.01-5.00 Sodium Fluoride 0.10-0.32 Lysozyme 0.01-5.00 Tetracal pyrophosphate 1.00-5.00 Preservative 0.20-0.30 Flavoring 0.10-1.50 Demineralized water rest 4. Toothpaste under item 1, characterized in that for its manufacture using the following components, mass. %:
Papain 0.01-5.00 Abrasive component 2.00-20.00 Humidifier 5.00-20.88 Ε-acetylaminocaproic acid sodium salt 0.001-5.00 Hydrocolloid 0.10-2.00 Surfactant 0.10-1.00 Hyaluronidase 0.01-5.00 Sodium Fluoride 0.10-0.32 Lysozyme 0.01-5.00 Tetracal pyrophosphate 1.00-5.00 Preservative 0.20-0.30 Flavoring 0.10-1.50 Demineralized water rest