RU2722306C1 - Composition for regulation of microelement metabolism in oral cavity - Google Patents

Abstract

FIELD: pharmaceuticals; hygiene.SUBSTANCE: group of inventions relates to an innovative synergetic complex for use in oral care products containing a combination of hydroxyapatite, bischofite, sea salt, magnesium aspartate, zinc gluconate and copper gluconate, as well as a tooth paste containing such a complex. Disclosed is a composition for use in an oral care agent containing, wt%: 1.00–40.0 of Ca-Mg-Zn hydroxyapatite; 0.01–4.00 of bischofite; 0.001–2.00 of sea salt of Israeli type 0; 0.001–2.00 combination of magnesium aspartate, copper gluconate, zinc gluconate. Oral care means can be presented by toothpaste, gel, spray, chewing gum, foam, elixir, ointment, balsam or rinse. What is also presented is a tooth paste containing the above composition. Group of inventions can be used in oral care, as well as for preventing dental, gum and / or oral cavity diseases.EFFECT: using the group of inventions, achieving remineralizing and antimicrobial effects, regenerating gum tissue effect, providing freshness of respiration, anti-edema and analgesic effects with masking of taste, activation of cell responses, maintaining locally stable pH, which again improves remineralization and promotes anti-caries effect.17 cl, 15 tbl, 4 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to an innovative synergistic complex, which is an oral composition containing a combination of hydroxyapatite, the natural mineral bischofite, sea salt, magnesium aspartate, zinc gluconate and copper gluconate. The invention can be used in caring for the oral cavity, as well as for the prevention of diseases of the oral cavity (teeth, gums, mucous membrane).

BACKGROUND

The condition of the oral cavity is important for overall health and well-being throughout life. Over the past decades, the main directions in the search for new solutions in dentistry have been the prevention and treatment of dental caries, as well as the prevention and treatment of non-carious diseases.

Tooth decay is a multifactorial disease caused by the simultaneous interaction of food sugars, plaque, the body and time. Dietary carbohydrates are metabolized by plaque bacteria, producing a number of organic acids (Geddes, 1975), causing a drop in pH inside the dental deposit. Below the “critical pH”, tooth enamel begins to undergo demineralization, and arising with a certain frequency of pH drop leads to the formation of an initial focus of caries, characterized by the loss of subsurface enamel minerals with a relatively intact surface layer (Arends and Christoffersen, 1986). With the further development of the lesion by acid demineralization, the enamel structure underlying the surface is destroyed and surface fractures and a clinically detectable cavity are formed. Ultimately, the lesion progresses to dentin and can lead to the destruction of the entire tooth.

Other contributing factors to dental caries are salivation, buffering capacity, i.e. the ability of saliva to neutralize acids and maintain pH, as well as the presence of certain protective enzymes and molecules in saliva (American Academy of Pediatric Dentistry, 2013). However, in the scientific literature, the mechanisms of demineralization-mineralization of enamel and the role of trace elements in these processes are not adequately disclosed.

The mineral component of tooth enamel is mainly substituted hydroxyapatite (HAP) calcium, the stoichiometric formula of which is Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ . Inside the enamel, a certain amount of ions can leave the HAP with the formation of elementary substitutions, for example, calcium with sodium, magnesium, zinc, etc .; carbonate can replace phosphate, and fluoride can replace hydroxyl (Featherstone, 1999; Robinson et al., 2000; Robinson, 2009). These defects and replacements can have a profound effect on the properties of HAP, especially with regard to its solubility at low pH. In particular, calcium-deficient and carbonate-rich regions of the crystal are particularly sensitive to acid demineralization, while fluorine substitution of hydroxyl can increase resistance to acid demineralization (Featherstone, Goodman and McLean, 1979). Biological apatites also include carbonated apatites, characterized by the presence of various amounts of substituting ions, either included in the apatite lattice or simply adsorbed on the surface of the crystal, including anionic ones (for example, F ^- , Cl ^- , SiO ₄ ^4- and СО ₃ ^2- ) and / or cationic substitutions (e.g., Na ⁺ , Mg ²⁺ , K ⁺ , Sr ²⁺ , Zn ²⁺ , Ba ²⁺ , Al ³⁺ ). In fact, nucleation and growth of calcium phosphates in biological systems occur in an environment rich in ions, which affects both the kinetics of crystallization and thermodynamics and, therefore, their stability (Cacciotti, 2015).

It has long been suggested that trace elements affect the cycles of demineralization-remineralization of teeth. The participation of trace amounts of metals in the process of dimenralization-remineralization of the tooth structure is based on the fact that the concentration of elements measured on the enamel surface (at a depth of 0-20 μm) is higher than the average value over the entire enamel. The lowest values are found for strontium, while the highest for lead.

The relationships between changes in the number of salivary micronutrients and the incidence of caries have been investigated in several works (Duggal, Chawlaand Curzon, 1991; Watanabeef al., 2011). In particular, the presence of caries turned out to be in inverse correlation with the level of Cu. It was shown that the level of enamel demineralization is inhibited by Cu (S .. Brookes et al., 2003), exhibiting a karyostatic effect. It was also shown that the level of zinc in saliva in children with active caries is significantly higher than in healthy children of the control group (Sekhri et al., 2018). Remineralizing ability has been established for fluoride, especially when the pH of saliva drops. Other elements such as phosphorus, copper, molybdenum, calcium, magnesium, barium, strontium and aluminum are also associated with low levels of caries. However, some elements, such as iron, manganese and potassium, are associated with a high incidence of caries. It is noteworthy that the most represented trace elements of enamel are also major in saliva (Na, Mg, K, and Zn) (Grad, 1954; Borella, Fantuzzi and Aggazzotti, 1994; Sekhri et al., 2018), illustrating the significance of studying the concentrations of trace elements in saliva. Several authors suggest that there is a relationship between the concentration of elements in saliva and the incidence of periodontal and dental caries in various population groups (Edgar, 1990; Duggal, Chawla and Curzon, 1991; Zalchik, VE, Bagirov, 1991; Borella, Fantuzzi and Aggazzotti, 1994; Hussein et al., 2013). Zaichk and Bagirov (Zalchik, VE, Bagirov, 1991) found that adults with a higher frequency of periodontal disease have an increased concentration of Fe, Sc, Mn, Cr, Co, Cu, Se, Ag, and Hg, as well as a decrease in the concentration of Zn in unstimulated saliva. Dugtal et al. (Duggal, Chawla and Curzon, 1991) found that the concentration of C showed a constant inverse dependence on the incidence of caries in children, while the elements of Fe and Mn showed a direct relationship with tooth decay. A very important indicator of the saliva state is the ionic strength, the value of which determines the activity of ions, including mineralizing components (Ca ²⁺ and HPO ₄ ^2- ). It was established that the activity indicators of Ca ²⁺ and NRA ₄ ^2- ions in saliva are much higher than in blood plasma, which determines the mineralizing function of the oral fluid. Thus, in assessing the mineralization and demineralization of tooth enamel, calcium and phosphorus concentration, pH, and ionic strength of saliva are important (Bekzhanova, 2009; Vijayaprasad, K.E., Ravichandra, K.S., Vasa, AA, Suzan, 2010; N. Li, M. Liu, 2011; Skripkina, 2011).

The presence of trace elements ions can not only affect the enamel remineralization processes. The cell wall of gram-negative bacteria is known to contain layers of both peptidoglycan and lipopolysaccharide, which affect the permeability of molecules (Gayathri et al., 2018). According to recent studies, ions present in some compositions can react with groups of -SH proteins, thereby participating in bacterial inactivation (Guzman, Dille and Godet, 2012). In explaining how ions can inhibit the growth of microorganisms, three mechanisms are considered (Hajipour et al., 2012). Firstly, this is the penetration of ions through the cell membrane in combination with a change in the regulation of ATP production and DNA replication. Secondly, the fixation of ions on cell membranes by electrostatic forces that disrupt the integrity of the cell and affect the free transport of protons and other molecules into and out of the cell. And finally, the induction of oxygen stress by the formation of free radicals (also called active forms of oxygen: ROS), which disrupt normal function and can irreversibly damage bacteria (their membranes, DNA and mitochondria), which leads to the death of bacteria.

Thus, the data indicate that the occurrence of a carious process in the tooth is preceded by a change in the quantitative composition of the substances of the oral fluid, namely, the ratio of phosphates, carbonates and trace elements changes. The trace elements present in minor amounts in enamel can also control the processes of remineralization-demineralization, the kinetics and thermodynamics of the growth of crystals of biological hydroxyapatite, however, the exact mechanism and optimal form of delivery of such components require study.

A change in the concentration of minerals in saliva also affects the homeostasis of the oral cavity and the remineralizing potential of the oral fluid. In addition, the effect of trace element ions on the viability of bacterial films opens up potential for the treatment of diseases of the oral cavity, which can be caused by their aberrant growth, namely in relation to lesions of tooth enamel in the neck of the teeth and adjacent gingival mucosa.

At the same time, decisions are still required on the development of a comprehensive tool that would provide a remineralizing, anti-caries, plaque-reducing effect on tooth enamel in the neck of the teeth and adjacent gingival mucosa, as well as an anti-inflammatory, desensitive, decongestant and regenerative effect on the gums of the mouth .

The authors of the present invention see the need and opportunity to solve this problem by creating an innovative combination for the oral cavity, consisting of the following components.

Hydroxyapatite is a close mineral to the apatite crystal of tooth enamel, known for use as a remineralizing agent against early caries damage (Tschoppe et al., 2011; de Carvalho et al., 2014; IIJIMA et al., 2017). Calcium phosphate is thought to work by infiltration into micropores during tooth decay, where it acts as a crystallization nucleus, continuously attracting large amounts of calcium and phosphate ions from oral fluids to the lesion, contributing to the natural remineralization processes (Amaechi and van Loveren, 2013; Van Loveren, C. MCDNJM Huysmans, A. Lussi, H.-P-Weber, 2013). In addition to remineralizing properties, studies on the local use of hydroxyapatite showed the presence of release properties that can be used to control biomimetic biofilms (Lelli et al., 2014; Kensche et al., 2017). Microorganisms have the ability to adhere to free particles of hydroxyapatite contained in a toothpaste or mouth rinse, and thus are removed from the oral cavity, eventually losing the ability to colonize enamel (Kensche et al., 2017). It is also known that hydroxyapatite forms a protective layer on the enamel surface (Lelli et al., 2014). Of all the phases of calcium phosphate, hydroxyapatite with the composition Ca ₅ (PO ₄ ) ₃ (OH) has the closest similarity to natural enamel (Enax and Epple, 2018). In this case, the Ca / P molar ratio is usually 1.67 (Alioui, Bouras and Bollinger, 2019). Additionally, ions such as Zn ²⁺ , Sr ²⁺ , Mg ²⁺ , Pb ²⁺ , Na ⁺ , CO ₃ ^2- , as well as water molecules can be artificially incorporated into the apatite crystal (Brown, PW, Constantz, 1994; Dorozhkin and Epple, 2002; Enax and Epple, 2018). The presence of some of these cations in the bones can be actively involved in the formation and reabsorption of bone.

In fact, deficiency of Mg2 + ions reduces the growth rate of osteoblasts (Rude et al., 2003), leading to a decrease in bone mass density, while Zn2 + ions contribute to bone formation, increasing this growth rate (Kawamura et al., 2000a). Magnesium - and zinc-substituted HAP materials have been shown to exhibit superior biocompatibility and biological properties. At the same time, it is known that calcium and magnesium are part of tooth enamel at least to a depth of 900 μm (Klimuszko et al., 2018), while there is a direct correlation between the concentration of magnesium and calcium in enamel at a depth of 150-900 μm.

Magnesium is present in tooth enamel mainly in the form of magnesium phosphate and is an element that affects the quality and anatomy of hard tooth tissues (Lagocka, R, Jakubowska, K, Lipski, M, Buczkowska-Radlinska, J, Chlubek, D, Opalko, 2003) . Magnesium ions inhibit crystal growth by replacing calcium ions in hydroxyapatite (Teruel et al., 2015), playing an important role in regulating the growth of hydroxyapatite crystals. This mineral may also affect alkaline phosphatase activity, which catalyzes the formation of the corresponding hydroxyapatite crystals and may inhibit the conversion of amorphous calcium phosphate to crystalline form. In addition, magnesium is also a component of the organic enamel matrix (Aoba, 1996). Hydroxyapatite doped with zinc and magnesium retains the structure of HAP, but the cationic substitution of metals leads to significant changes in crystal shape and size (Gopi et al., 2012; Kaygili and Keser, 20IS). These additives contribute to the increase in the inhibitory activity of HAP against C. albicans (Alioui, Bouras and Bollinger, 2019). It was shown that Zn-HAP with the amount of Zn ions less than 1.2 wt. % represent effective bioactivity and antibacterial properties (Ito et al., 2000; Kawamura et al., 2000b; Sogo et al., 2002; Stanic et al., 2010), in particular on the growth of bacteria and fungi, including E. coli, S. aureus, Candida albicans (C. albicans) and Streptococcus mutans (S. mutans) (Chung et al., 2006; Velard et al., 2010; Thian et al., 2013), with a zinc content of more than 1000 ppm for the manifestation of an antimicrobial effect. According to the mechanism of action, it was suggested that Zn ions form strong bonds with thiol, imidazole, amine, and carboxyl groups, causing structural changes and affecting the permeability and transport of membranes, which leads to cell death (Stanic et al., 2010).

Thus, for this composition, hydroxyapatite, substituted with magnesium and zinc, with improved properties, was selected.

The concept of remineralization of calcium phosphates individually, as well as in combination with other substitution cations, is implemented in modern oral care products.

Bischofite is a natural mineral mineral, which includes almost 70 macro- and microelements. At 80-90% bischofite consists of magnesium salts (magnesium chloride 420-430 g / l, density 1.30-1.32 g / cm3, pH: 4.5-4.7). It has been used on the territory of the former USSR as a balneological treatment with topical application since the 1980s (Sysuev BB. Technological and pharmacological studies of the bischofite mineral as a source of magnesium-containing medicines. Thesis for the degree of Doctor of Pharmaceutical Sciences. Volgograd State Medical University, 2012). It is found in large quantities in the mud and brine of Lake Elton in the Volgograd Region. A number of publications have shown the beneficial effects of bischofite in various conditions. So, the anti-inflammatory effect on the model of atopic dermatitis was demonstrated (Spasov AA, Mazanova LS, Motov AA, Orobinskaya TA, Sysuev BB. The effect of bischofite mineral ointment on the course of contact allergic dermatitis caused by 2,4-dinitrochlorobenzene. Experimental and Clinical Pharmacology 2009; 72: 37-9), in clinical trials for rheumatoid arthritis (Zborovsky AB, Martemyanov V. F, Sidorova EA, Brain EE, Zborovskaya IA. Bischofite in the treatment of patients with rheumatoid arthritis. Therapeutic Archive 2003; 75: 29-32). In relation to the skin, bischofite had a regenerating effect in cryotrauma (Spasov AA, Mazanova LS, Motov AA, Orobinskaya TA, Sysuev BB. The regenerating activity of the hydrophilic ointment of the mineral bischofite in acute local cryotrauma. Experimental and Clinical Pharmacology 2008; 71: 39-41). In animal models and in clinical studies, it was shown that preparations containing bischofite have an immunomodulating effect, stimulating phagocytosis in the damaged oral mucosa, and suppress the inflammatory process in gingivitis and periodontitis (AA Spasov, ES Temkin, O. Ostrovsky, Kalinina N.V., Gerchikov L.V., Mikhalchenko V.F., et al. Experimental and clinical rationale for the use of the drug polycatan for periodontal diseases. , Smirnova L.A., Gerchikov L.V., Temkin E.S. Anti-inflammatory effect of the bischofite mineral.Experimental and Clinical Pharmacology 1998; 61: 64-6.). On animals, it has been shown that bischofite has low toxicity [Sysuev BB, Iezhitsa I.N., Lebedeva S.A. The study of the toxicity of oral forms of bischofite mineral solution. Basic Research 2013: 680-3; Sysuev B.B., Spasov A.A., Mazanova L.S. Toxicity study of purified bischofite mineral solution. Modern problems of science and education 2013; 1.), Which allowed to strengthen the concept of the use of bischofite-based drugs in clinical practice. There are technologies for producing bischofite for creating various dosage forms (Sysuev BB Technological and pharmacological studies of the mineral bischofite as a source of magnesium-containing medicines. Thesis for the degree of Doctor of Pharmaceutical Sciences. Volgograd State Medical University, 2012).

Magnesium, one of the components of bischofite, is an essential macrocell, a universal regulator of biochemical and physiological processes, which is determined, first of all, by its cofactor role in enzymes and modulating function in ion channels. Being the second most common cation inside the cell, magnesium is involved in energy, plastic and electrolyte metabolism. According to modern concepts, magnesium deficiency leads to changes that are key in the development of a number of pathological conditions: deficiency of functionally active enzymes; the development of generalized inflammation with subsequent systemic dysplasia of the connective tissue; a critical change in the Ca: Mg ratio and, as a consequence, a violation of electrolyte metabolism, the main biochemical and physiological processes. Magnesium is believed to play a role in caries formation, bone deposition and mineralization (Lilley et al., 200S), and also directly stimulates the proliferation of osteoblasts (Suchanek et al., 2004). Sodium chloride is the second most common bischofite component. It is known that this salt has an antibacterial effect, primarily due to its osmotic effect, and also affects the charge on the surface of demineralized dentin. Recently, it has also been shown that, at certain concentrations, sodium chloride alters the expression of genes encoding glycosyltransferases in S. mutans, thereby regulating the potential of biofilm attachment to the tooth surface (Nagavi-Alhoseiny et al., 2019). In a minor amount, bischofite contains potassium sulfate and magnesium sulfate - soluble salts. Potassium-containing toothpastes are known to have a desensitizing and calming effect, primarily due to a decrease in the conduction in the pulp nerve (Hu et al., 2018). Sulfate can regulate the remineralization processes in tooth enamel due to its effect on phosphate ions (Liu et al., 2012).

Sea salt - consists mainly of sodium chloride (> 99%), with minor inclusions of magnesium, calcium, strontium, lithium, iron, molybdenum, zinc, selenium, lead, copper, manganese and cobalt (Condo, 1999). The mechanism of action of salt is based on several activities: stimulation of salivation, hydro-salt metabolism, decongestion, and remineralization. In human saliva, the concentration of sodium chloride is 0.006-0.46%. Toothpastes and rinses typically contain 5-15% of sea salt or sodium chloride, stimulating intense salivation, which has a protective effect in the oral cavity. Local high salt concentrations (hypertonic solutions), due to dehydration of the skin or the mucosa, trigger the mechanism by which cells require water and thus trigger hydro-salt metabolism at the cellular level. Osmotic action or metabolism allows minerals to be absorbed through the skin, excess fluid is drained, metabolic waste is removed and effective detoxification occurs. Sea salt has an astringent effect, promoting healing by reducing inflammation and reducing gingival tissue. Minerals of natural sea salt help to heal inflamed skin and mucous membranes due to their anti-inflammatory properties. Natural sea moth also has antiseptic and antibacterial properties. Due to the osmotic effect, sea salt can penetrate through semipermeable bacteria membranes, causing wrinkling and dehydration. Also, the osmotic effect of sea salt explains its decongestant effect and the reduction in gummy wrinkling that is present with gingivitis. Mouthwashes with sea salt also have a beneficial effect due to an increase in pH in the mouth, which helps to reduce colonization by pathogenic bacteria.

Aspartate of Magnesium. Magnesium is believed to play a role in caries formation, bone deposition and mineralization (Lilley et al., 2005), and also directly stimulates the proliferation of osteoblasts (Suchanek et al., 2004). For aspartic acid, it was shown that it can accelerate the kinetics of crystallization of stabilized apatite and crystallization in the zones of microcracks inside collagen fibrils (Matsumoto et al., 2006). According to previous studies, acidic amino acids have been shown to enhance osteoblast activation and mineralization processes (Sarig, 2004; Boanini et al., 2006). Aspartic acid is one of the essential amino acids in the human body, which is widely used as a biochemical reagent (Rajda et al., 1999; Ohzeki et al., 2007) and their food and saliva may be available (Rajda et al., 1999). However, the direct addition of acid to the composition can have a negative effect on the stability of the formulation, as well as cause increased tooth sensitivity, therefore, the use in the form of salt seems more appropriate.

Trace elements, such as zinc and copper, are actively involved in the enzyme systems responsible for bone matrix exchange (Branca, Valtuefla and Vatuena, 2001). Zinc is an integral part of approximately 300 enzymes, including those necessary for bone metabolism (bone alkaline phosphate) (Vallee and Falchuk, 1993). Copper is another trace element involved in bone metabolism as a cofactor of lysyl oxidase, one of the main enzymes involved in collagen crosslinking. Animal studies suggest that Cu deficiency is associated with decreased bone strength and deterioration in bone quality, leading to osteoporotic lesions (Medeiros et al., 1997).

Zinc gluconate acts as an effective source of zinc, and in this vein is used in toothpaste formulations. Zinc causes various changes in oral microorganisms due to its antibacterial effect, reducing plaque and having an anti-caries effect (Kim, 2007). Zinc is the most commonly used metal for inhibiting the formation of volatile sulfur compounds (LSS), due to its low toxicity and lack of staining effect. It is believed that zinc forms low solubility sulfides with the precursors of LSS, thus inhibiting the production of LSS until zinc ions are available for reaction in the oral cavity. Moreover, the initial solubility of zinc salts in water does not affect its inhibitory properties. Blocking of H2S release in the oral cavity occurs. The use of zinc gluconate in palatal adhesive tablets is known to be effective in reducing odor by the inactivation mechanism of volatile sulfur compounds (Sterer et al., 2008). The direct use of zinc gluconate in pastes can also effectively reduce the appearance of bad breath, which has been successfully shown in a human study (Young and Jonski, 2011). In addition, there is evidence that zinc can act as an antimicrobial enhancer of other components. In addition, zinc is an indispensable component of many specific enzymes (Keilin, D., Mann, 1940; Vallee, L., Wacker, 1970), and is also involved in the early phases of collagen metabolism (McClain et al., 1973). It was shown that the level of zinc in damaged gum tissue increases. In addition, zinc levels the cessation of collagen synthesis under the influence of volatile sulfur compounds, and zinc chloride inhibits the degradation of collagen mediated by matrix metalloprotease in dentin (Toledano et al., 2012). It is known that methyl mercaptan (a representative of LSS) suppresses the synthesis of intracellular and extracellular collagen in in vitro gum fibroblasts (Johnson, Yaegaki and Tonzetich, 1996). The addition of zinc eliminates this negative effect. It has been suggested that the use of zinc reduces oral inflammation and may be an alternative treatment for recurrent aphthous stomatitis (Kim et al., 2015). Zinc chloride also has antioxidant and anti-inflammatory activities. In a zinc-deficient environment, the morphology and polarization of the gingival fibroblasts are disturbed, oxidative stress develops, proliferation decreases, and caspase-3 is activated (Rudolf and Cervinka, 2010). In (Williamson, Yukna and Gandor, 1984), it was shown that oral administration of zinc promotes faster healing of wounds after biopsies of gum tissue taken from dogs. At the same time, the concentration of zinc in damaged gums significantly increases compared to healthy ones even without zinc. Etzel et al. (Etzel et al., 1982) showed that hamsters injected with endotoxins from two bacterial strains concentrated zinc in the gum tissue. Similar in vitro results by Aleo (Etzel et al., 1982) showed that zinc supplementation can reverse the detrimental effects of endotoxin on cultured fibroblasts and that zinc protects against endotoxin exposure. Wallace et al. (Wallace, Ringsdorf and Cheraskin, 1978) described enhanced biopsy wound healing when zinc was administered to their patients. Zinc also has a protective effect on inducible colitis in vivo (Rohweder et al., 1998).

The effect of trace elements, such as zinc and copper, on the demineralization and remineralization of teeth has been described previously (Abdullah et al., 2006; Churchley et al., 2011). Zinc has been reported to decrease enamel solubility (Churchley et al., 2011; Lynch, 2011). It has also been suggested that zinc is incorporated into enamel during in situ remineralization, despite a moderate level of increased zinc concentration (Matsunaga et al., 2009). Brooks et al. also demonstrated that copper has a direct protective effect on the dissolution of enamel in an acidic medium (S.J. Brookes et al., 2003).

The organic form of the zinc salt is selected in the present composition (Sierpinska et al., 2014).

Copper gluconate. It is known that soluble copper compounds, like zinc, bind to sulfide anions in an aqueous medium, being strong ligands, and their activity is comparable (Waer, 1997). However, there is evidence that, unlike zinc, copper ions also inhibit the formation of methyl mercaptan. It has also been demonstrated that Cu inhibits acid production by acidogenic bacteria (Stephan, 1949), thus reducing the concentration of Cu affects acid production and its incorporation provides an anticaries effect. It is known that the gluconate anion can chelate Ca ^{+ 2} and other metals. Its inclusion in the composition may contribute to the formation of calcium-decipitous apatite with an increase in the possibility of other divalent metals to be incorporated into remineralizing enamel, which allows achieving a closer to the biological composition of apatite. Also, due to the chelating effect of gluconate in relation to calcium ion, the composition of the composition suggests a more effective local release of zinc and copper, increasing their effective concentration near the enamel. Third aspect: gluconate chelates calcium, increasing the negative charge on apatite, and thereby contributing to the involvement of aspartate to create a new nucleation center and activate the remineralizing process. All these features can explain the mechanism of synergistic action of the claimed multicomplex.

SUMMARY OF THE INVENTION

In the first embodiment, the claimed invention relates to compositions for use in the composition of means for caring for the oral cavity, containing,% wt .:

Hydroxyapatite Ca-Mg-Zn 1.00-40.0, Bischofite 0.01-4.00, Israeli sea salt type 0 0.001-2.00, Magnesium Aspartate, Copper Gluconate, Zinc Gluconate 0.001-2.00.

The oral care product may be a toothpaste, gel, spray, chewing gum, foam, elixir, ointment, balm or rinse aid.

Hydroxyapatite Ca-Mg-Zn may be contained in an amount of about,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

Hydroxyapatite Ca-Mg-Zn may be contained in an amount,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 , 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

Bischofite can be contained in an amount of about,% wt .: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45 , 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3 , 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6 , 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0.

Bischofite may be contained in an amount, wt%: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0.

Israeli sea salt type 0 may be contained in an amount of about,% wt: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0, 4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1, 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.

Israeli sea salt type 0 may be contained in an amount,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0, 4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1, 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.

The combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate can be contained in an amount of about,% wt: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0, 35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.

The combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate may be contained in an amount, wt%: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0, 35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2.

Magnesium aspartate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount of about,% wt: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

Magnesium aspartate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount, wt%: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

Copper gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate may be contained in an amount of about,% wt: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

Copper gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount, wt%: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

Zinc gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount of about,% wt: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

Zinc gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate may be contained in an amount, wt%: 0.01, 0.05, 0.1, 0.5, 1.5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 99.

The combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate may contain from about 0.2 to about 0.5% wt. magnesium, from about 0.05 to about 0.1% wt. copper, from about 0.4 to about 0.9% wt. zinc. Alternatively, the combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate may contain from 0.2 to 0.5% wt. magnesium, from 0.05 to 0.1% wt. copper, from 0.4 to 0.9% wt. zinc. For example, about 0.2, about 0.3, about 0.4, or about 0.5% wt. magnesium about 0.05% wt., about 0.01% wt., about 0.02% wt., about 0.03% wt., about 0.04% wt., about 0.05% wt., about 0 , 06% wt., About 0.07% wt., About 0.08% wt., About 0.09% wt. or about 0.1% wt. copper; about 0.4% wt., about 0.5% wt., about 0.6% wt., about 0.7% wt., about 0.8% wt. or about 0.9% wt. zinc. Alternatively, 0.2, 0.3, 0.4 or 0.5% wt. magnesium 0.05% wt., 0.01% wt., 0.02% wt., 0.03% wt., 0.04% wt., 0.05% wt., 0.06% wt., 0 , 07% wt., 0.08% wt., 0.09% wt. or 0.1% wt. copper; 0.4% wt., 0.5% wt., 0.6% wt., 0.7% wt., 0.8% wt. or 0.9% wt. zinc.

In a second embodiment, the claimed invention relates to a toothpaste containing the composition of the invention.

Technical effects from the use of the claimed composition are as follows.

Remineralizing effect - improvement of enamel remineralization processes due to:

- inclusion of cations of magnesium and zinc from bischofite and gluconate, which are replaced in hydroxyapatite, change its crystalline and morphological properties in a positive direction and will maintain an effective concentration for calcium-magnesium substituted hydroxyapatite;

- inclusion of magnesium aspartate in the composition, which, firstly, being an organic aminoxylot, can be a seed for new nucleation centers, and secondly, it will increase the local effective concentration of magnesium;

- inclusion of gluconate, which will chelate calcium from apatite, ensuring the presence of centers of elementary substitution in hydroxyapatite.

Also, the remineralization process helps to reduce the sensitivity of tooth enamel. The effect is achieved by restoring the enamel structure - the result of filling microdamages with hydroxyapatite minerals.

Antimicrobial effect - provides increased antimicrobial activity of tooth enamel due to the inclusion of soluble zinc gluconate, where zinc has a proven antimicrobial activity. In addition, due to the fact that gluconate chelates calcium, more targeted delivery of zinc to tooth enamel will be provided, providing a more effective antimicrobial effect on biofilms of plaque and gums.

Ensuring fresh breath by blocking the LSS due to the inclusion of zinc and copper ions.

The gum tissue regenerating effect is due to the provision of enhanced collagen synthesis in the gum tissue due to the inclusion of zinc and copper ions.

Provides a more powerful decongestant and analgesic effect with a taste mask (in contrast to products with a higher content of sea salt) due to increased ionic strength in the near-gum space, as well as through the use of organic zinc (and magnesium) salt.

Provides activation of cellular reactions, including by increasing the activity of magnesium-, zinc- and copper-dependent enzymes.

It ensures the maintenance of locally stable pH by creating a buffer tank in the presence of an increased amount of divalent metals, which again increases the remineralization efficiency and contributes to the anti-caries effect.

Provides increased salivation after application of the paste, and with it an increase in the remineralizing ability of the composition and anti-caries effect.

DETAILED DESCRIPTION OF THE INVENTION

The claimed invention relates to a composition and toothpaste containing it for the prevention of diseases of the oral cavity (teeth, gums, mucous membrane).

In the first embodiment, the claimed invention relates to compositions for use in the composition of means for caring for the oral cavity, containing,% wt .:

Hydroxyapatite Ca-Mg-Zn 1.00-40.0, Bischofite 0.01-4.00, Israeli sea salt type 0 0.001-2.00, Magnesium Aspartate, Copper Gluconate, Zinc Gluconate 0.001-2.00.

As an alternative, the invention relates to a composition for use in an oral care composition containing,% by weight:

Hydroxyapatite Ca-Mg-Zn 1.00-40.0, Bischofite 0.01-4.00, Israeli sea salt type 0 0.001-2.00, Magnesium Aspartate, Copper Gluconate, Zinc Gluconate 0.001-2.00, filler (excipients) rest.

As an alternative, the invention relates to a composition for use in an oral care composition containing,% by weight:

Hydroxyapatite Ca-Mg-Zn 1.00-2.0, Bischofite 0.01-4.00, Israeli sea salt type 0 0.001-2.00, Magnesium Aspartate, Copper Gluconate, Zinc Gluconate 0.001-2.00, filler rest,

where the filler is optionally water.

As an alternative, the invention relates to a composition for use in an oral care composition containing,% by weight:

Hydroxyapatite Ca-Mg-Zn 1.00-2.0, Bischofite 0.01-4.00, Israeli sea salt type 0 0.001-2.00, Magnesium Aspartate, Copper Gluconate, Zinc Gluconate 0.001-2.00, filler 90.0-98.988,

where the filler is optionally water.

Hydroxyapatite Ca-Mg-Zn (hydroxyapatite enriched with magnesium and zinc; zinc-magnesium substituted (modified) hydroxyapatite; calcium / magnesium / zinc hydroxyapatite complex) is a commercially available product that is already used in toothpastes (eg, SILVER from SPLAT). Calcium hydroxyapatite (HAP) - Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ - an analogue of the mineral component of bone tissue - is widely used in medicine and cosmetology. The sizes of HA crystals in dentin are smaller than in enamel. HAP is biocompatible with the environment of the human body, osteoconductive and is an ideal inert carrier for cell cultures. To impart specific properties, chemical modification is used, in particular, anionic and cationic calcium substitution. Of particular interest is modified calcium hydroxyapatite. The choice of ions is related to their biological role in the body. A decrease in the specific surface area with an increase in the content of the replacement ion (zinc, magnesium) is associated with an increase in the degree of aggregation of particles. Smaller particles are known to have a larger radius of curvature of the surface and, therefore, greater activity and degree of aggregation. With an increase in the amount of the replacement ion in the structure of the HAP, an increase in the particle size occurs. For zinc and magnesium-containing hydroxyapatite with a degree of cationic substitution of up to 0.2%, partial replacement of calcium with zinc and magnesium in hydroxyapatite leads to a decrease in particle size, an increase in the surface area and biological activity of zinc and magnesium-substituted hydroxyapatite, and therefore their use as components provides greater efficiency. The results of studies of biological activity for zinc-substituted hydroxyapatite indicate a significantly greater biological (bactericidal) activity compared with GA. Such a modified GA is available on the market.

Hydroxyapatite Ca-Mg-Zn may be contained in an amount of about,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10.11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40; or hydroxyapatite Ca-Mg-Zn may be contained in an amount,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40.

Bischofite, such as granular bischofite, Ancient Sea salt, is a commercially available product already used in toothpastes (eg BishEffect from TOV "JARDIN KOCMETIK"). Bischofite can be contained in an amount of about,% wt .: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45 , 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3 , 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6 , 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0; or bischofite may be contained in an amount,% wt .: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45 , 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3 , 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6 , 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0.

Israeli Sea Salt Type 0 is a commercially available product. Israeli sea salt type 0 may be contained in an amount of about,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0 , 4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; or Israeli sea salt type 0 may be contained in an amount,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0 , 4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1 , 2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.

Magnesium Aspartate, Copper Gluconate, Zinc Gluconate are each commercially available products from various suppliers. The combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate can be contained in an amount of about, wt%: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0 , 35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; or a combination of Magnesium Aspartate, Copper Gluconate, Zinc Gluconate may be contained in an amount, wt%: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0.3, 0 , 35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1 , 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.

Magnesium aspartate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount of about,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 70, 75, 80, 85, 90, 95 or 99; or Magnesium aspartate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate may be contained in an amount, wt%: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 , 70, 75, 80, 85, 90, 95, or 99.

Copper gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount of about, wt%: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 70, 75, 80, 85, 90, 95 or 99; or Copper gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate may be contained in an amount, wt%: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 , 70, 75, 80, 85, 90, 95, or 99.

Zinc gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate can be contained in an amount of about,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 70, 75, 80, 85, 90, 95 or 99; or Zinc gluconate in the indicated combination Magnesium aspartate, Copper gluconate, Zinc gluconate may be contained in an amount, wt%: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 , 70, 75, 80, 85, 90, 95, or 99.

In a second embodiment, the claimed invention relates to a toothpaste containing the composition of the invention.

EXPERIMENTAL PART

The examples included in this section are not limiting of the claimed invention and are given only for the purpose of illustrating and confirming the achievement of the expected technical results. These examples are one of the many experimental data obtained by the inventors, which confirm the effectiveness of the funds within the scope of the invention.

The following clinical trials were conducted to evaluate the effectiveness.

Example 1

In the experimental groups with the participation of patients, compositions were used that included the claimed complex containing hydroxyapatite (hydroxyapatite enriched with calcium, magnesium and zinc) as a 10% suspension - 5% by weight, the natural mineral bischofite - 1.34%, as active ingredients. Israeli sea salt type 0-0.1%, the combination of magnesium aspartate + copper gluconate + zinc gluconate - 0.1% (Table 1).

Toothpaste with the composition shown in Table No. 2 was used as a base for the inclusion of components.

A prospective, randomized, double-blind study was conducted on 120 subjects (64 men and 56 women), randomized into three equal sex and age groups. Patients used toothpaste compositions 2 times a day for 6 weeks.

The parameter for evaluating the effectiveness of the drugs was the average gum bleeding index (GBI), determined by the dentist. In addition, the functional state of enamel was evaluated by determining the acid solubility rate of enamel using calcium and KOSRE-gest (clinical determination of enamel remineralization rate).

For all quantitative data, the group arithmetic mean (M), median (Me), standard deviation (SD) and standard error of the mean (SEM), interquartile ranges, 90% CI were calculated. The results were processed using IBM SPSS Statistics 22.0 software (StatSoft, Russia). The probability of differences in the means of the groups was determined using the Mann-Whitney test. Differences were considered significant at a significance level of p <0.05.

Results.

6 weeks after the start of the study, pronounced changes in the evaluated indicators in the study groups were observed. In group 1, which used a composition with a complex of hydroxyappatite (hydroxyapatite enriched with calcium, magnesium and zinc) in the form of a 10% suspension - 5% by weight, the natural mineral bischofite - 1.34%, Israeli sea salt type 0-0.1%, the combination of magnesium aspartate + copper gluconate + zinc gluconate, the GBI value at the end of the study was 0.04 ± 0.02, which is less than the initial values (0.16 ± 0.03; P <0.05). In group 2, which used the combination of magnesium aspartate + copper gluconate + zinc gluconate, a mild GBI change was noted; at the end of the study, its value was 0.12 ± 0.03 compared with the initial values (0.17 ± 0.02; P > 0.05), in group 3, which used the composition with hydroxyapatite, no significant changes were also observed - GBI at the beginning of the study was 0.16 ± 0.03, at the end of the study - 0.15 ± 0.02; P> 0.05.

Thus, the use of paste with a complex of hydroxyapatite (hydroxyapatite enriched with calcium, magnesium and zinc) in the form of a 10% suspension is 5% by weight, the natural mineral bischofite is 1.34%, Israeli sea salt is 0-0.1%, a combination magnesium aspartate + copper gluconate + zinc gluconate led to a decrease in the severity of gingivitis, moreover, this effect was reliably expressed in comparison with the use of hydroxyapatite and the combination of magnesium aspartate + copper gluconate + zinc gluconate, which indicates a synergistic effect of the components included in the complex.

When analyzing the functional state of enamel, the following features were identified.

After applying toothpaste with a complex of hydroxyapatite (hydroxyapatite enriched with calcium, magnesium and zinc) in the form of a 10% suspension - 5% by weight, natural bischofite mineral - 1.34%, Israeli sea salt type 0-0.1%, aspartate combination magnesium + copper gluconate + zinc gluconate enamel remineralization rate increased 4 times, which indicates high remineralizing abilities of saliva under the influence of paste (P <0.05). In group 2, the remineralizing ability of the composition in combination with the basic composition of toothpaste did not significantly change, while in group 3 the remineralizing function increased by 2.3 times (P <0.05).

The rate of acid solubility of enamel on calcium was determined using the acid biopsy method. The maximum decrease in calcium yield occurred in the paste group with the hydroxyapatite complex (hydroxyapatite enriched with calcium, magnesium and zinc) in the form of a 10% suspension - 5% by weight, natural bischofite mineral - 1.34%, Israeli sea salt type 0- 0.1 %, the combination of magnesium aspartate + copper gluconate + zinc gluconate - at the beginning of the study 45.0 μg / ml, after applying the paste 33% less - 30 μg / ml. In group 2, a decrease of 9% was observed; in group 3, a significant decrease of 14.1% was observed.

Thus, the use of the hydroxyapatite complex (hydroxyapatite enriched with calcium, magnesium and zinc) in the form of a 10% suspension is 5% by weight, the natural mineral bischofite is 1.34%, Israeli sea salt is 0-0.1%, a combination of magnesium aspartate + copper gluconate + zinc gluconate allows to improve the functional properties of enamel (the remineralization rate increased by 4 times, and the acid solubility rate of enamel fell by 33%) due to the reliable synergistic action that make up the complex of components, which, in turn, effectively affects on a decrease in the sensitivity of tooth enamel.

Example 2

In the experimental groups with the participation of patients, compositions were used that included the claimed complex containing hydroxyapatite (hydroxyapatite enriched with calcium, magnesium and zinc) as a 10% suspension - 5% by weight, the natural mineral bischofite - 1.34%, as active ingredients. Israeli sea salt type 0-0.1%, the combination of magnesium aspartate + copper gluconate + zinc gluconate - 0.1% (Table No. 3).

As a base for the inclusion of components used toothpaste with the composition shown in Table No. 2 (Example 1).

A prospective, randomized, double-blind study was conducted on 120 subjects (58 men, 62 women) in 5 equal age and gender groups. Patients used toothpaste compositions 2 times a day for 8 weeks. The parameter for evaluating the effectiveness of the drugs was the average gum bleeding index (GBI), determined by the dentist. Also, to assess the oral carioresensibility, we used the parameter of the concentration of lactobacilli and S. mutans in saliva and plaque, showing the risk threshold for tooth decay, as well as the pH of saliva, which reflects the salivary buffer capacity and salivation rate.

At the initial examination, the following distribution of the presence of S. mutans in plaque and acidophilic bacteria in saliva was revealed in patients (Table No. 4).

At the end of the study, a significant and significant decrease in the level of streptococci in plaque and lactobacilli in stimulated saliva was observed in patients in the composition group. In the remaining groups, carioresistance indicators for S. mutans did not show a significant decrease, while for the level of acidophilic bacteria in saliva, a significant improvement was observed in all groups; however, the maximum effect was observed in group 1, and its value significantly differed from the values in the groups of monocomponents of the complex (Table No. 5).

When assessing the buffer capacity of saliva before the start of the study, the following distribution was observed in groups (Table No. 6).

After 8 weeks of applying the toothpastes of the experimental groups, the following changes were observed (Table No. 7).

A significant change in the buffer capacity was recorded in group 1, while in group 3 a co-directional correction of the buffer capacity was also observed, but only at the trend level. The salivation rate also significantly improved in the groups of the claimed composition, as well as in the groups containing sea salt and bischofite, while in groups 2 and 5 no significant differences were observed. Since in group 1 the most pronounced effect was observed in terms of the salivary buffer capacity and salivation rate, it can be concluded that the effect is achieved due to the synergistic action of the components of the composition, providing increased resistance of the oral cavity to plaque formation, as well as the development of gingivitis and caries.

Example 3

In the experimental groups with the participation of patients, compositions were used that included the claimed complex containing hydroxyapatite (hydroxyapatite enriched with calcium, magnesium and zinc) as a 10% suspension - 5% by weight, the natural mineral bischofite - 1.34%, as active ingredients. Israeli sea salt type 0-0.1%, the combination of magnesium aspartate + copper gluconate + zinc gluconate - 0.1% (Table No. 8).

As a base for the inclusion of components used toothpaste with the composition shown in Table No. 2 (Example 1).

A prospective, randomized, double-blind study was conducted on 50 subjects (24 men, 26 women) in 2 equal sex and age groups. Patients used toothpaste compositions 2 times a day for 10 weeks. The parameter for evaluating the effectiveness of the action of toothpaste compositions was saliva pH, which reflects the salivary buffering capacity and salivation rate.

When assessing the buffer capacity of saliva before the start of the study, the following distribution was observed in the groups (Table No. 9).

After 10 weeks of applying the toothpastes of the experimental groups, the following changes were observed (Table No. 10).

A significant change in buffer capacity and an increase in the salivation rate were recorded in the group with the claimed composition, while no significant differences were found in the placebo group. Thus, in terms of the salivary buffer capacity and salivation rate, it can be concluded that the observed effect is achieved due to the uniqueness of the action of the components of the composition, providing increased resistance of the oral cavity to plaque formation, as well as the development of gingivitis and caries due to the effect on saliva and salivation rate.

Example 4

In the experimental groups with the participation of patients, compositions were used that included the claimed complex containing calcium hydroxyapatite enriched with magnesium and zinc as active ingredients in the form of a 10% suspension - 5% by weight, natural bischofite mineral - 1.34% wt., 0 , 1% wt. Israeli sea salt type 0, 0.0024-0.006% May magnesium aspartate, 0.00035-0.00070% May copper gluconate, 0.0028-0.0070% May zinc gluconate (Table No. 11).

As a base for the inclusion of components used toothpaste with the composition shown in Table No. 2 (Example 1).

A prospective, randomized, double-blind study was conducted on 50 subjects (28 men, 22 women) in 2 equal sex and age groups. Patients used toothpaste compositions 2 times a day for 8 weeks. The parameters for assessing the effectiveness of the claimed complex were the level of lactobacilli and Streptococcus mutans in saliva and plaque, showing the risk threshold for tooth decay, as well as saliva pH, which reflects the salivary buffer capacity and salivation rate.

At the initial examination, the following distribution was revealed in patients according to the presence of S. mutans in plaque and acidophilus bacteria in saliva (Table 12).

At the end of the study, a significant and significant decrease in the level of streptococci in plaque and lactobacilli in stimulated saliva was observed in patients in the composition group. In the group without the claimed complex, the carioresistance indicators for S. mutans showed a tendency to decrease, while the level of acidophilic bacteria in saliva showed a significant improvement in this group; however, the effect in the group of the claimed complex was significantly higher than in the group of pasta of the basic composition (Table 13).

When assessing the buffer capacity of saliva and the rate of salivation before the start of the study, the following distribution was observed in groups (Table No. 14):

After 8 weeks of applying the toothpastes of the experimental groups, the following changes were observed (Table No. 15).

A significant change in buffer capacity and an increase in salivation rate were recorded in the group with the claimed composition, while in the group with the basic composition, no significant differences were found. Thus, in terms of the salivary buffer capacity and salivation rate, it can be concluded that the observed effect is achieved due to the uniqueness of the components of the claimed complex, providing increased resistance of the oral cavity to plaque formation, as well as the development of gingivitis and caries due to the effect on the buffer saliva capacity and salivation rate.

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Claims (18)

1. Composition for use in the composition for the care of the oral cavity, containing,% wt.: Hydroxyapatite Ca-Mg-Zn 1.00-40.0 Bischofite 0.01-4.00 Israeli sea salt type 0 0.001-2.00 Combination of magnesium aspartate, copper gluconate, zinc gluconate 0.001-2.00 2. The composition according to p. 1, where the means for caring for the oral cavity is a toothpaste, gel, spray, chewing gum, foam, elixir, ointment, balm or rinse. 3. The composition according to p. 1, where the hydroxyapatite Ca-Mg-Zn is contained in an amount of about,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40. 4. The composition according to p. 3, where the hydroxyapatite Ca-Mg-Zn is contained in an amount,% wt .: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40. 5. The composition according to p. 1, where bischofite is contained in an amount of about,% wt .: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35 , 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4 , 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7 , 3.8, 3.9 or 4.0. 6. The composition according to p. 5, where bischofite is contained in an amount,% wt .: 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9 or 4.0. 7. The composition according to p. 1, where the Israeli sea salt type 0 is contained in an amount of about,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0 , 3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9 , 1, 1,1, 1,2, 1,3, 1,4, 1,5, 1,6, 1,7, 1,8, 1,9 or 2. 8. The composition according to p. 7, where the Israeli sea salt type 0 is contained in an amount,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0.25, 0, 3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2. 9. The composition according to p. 1, where the combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount of about,% wt .: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0 , 25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85 , 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2. 10. The composition according to p. 9, where the combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount, wt%: 0.001, 0.005, 0.01, 0.015, 0.1, 0.15, 0.2, 0, 25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2. 11. The composition according to p. 1, where the magnesium aspartate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount of about,% wt .: 1,5, 10, 15, 20, 25, 30, 35, 40, 45 , 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 12. The composition according to p. 11, where the magnesium aspartate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 13. The composition according to p. 1, where the copper gluconate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount of about,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 , 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 14. The composition according to p. 13, where the copper gluconate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 15. The composition according to p. 1, where the zinc gluconate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount of about,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45 , 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 16. The composition according to p. 15, where the zinc gluconate in the specified combination of magnesium aspartate, copper gluconate, zinc gluconate is contained in an amount,% wt .: 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 99. 17. Toothpaste containing the composition according to any one of paragraphs. 1-16.