RU2327445C1 - Transdermal dentifrice water and related method of production - Google Patents

Abstract

FIELD: medicine; stomatology.

SUBSTANCE: transdermal dentifrice water contains gelling component, preserving agents, glycerin, biologically active substances, liposomes, bioflavonoid-antioxidant-haw extract, odorant, water, additionally it contains anion-active surface-active substance - lauryl sulfate, vegetable oil, paraform, emulsifier - polyethylene glycol, ammonium salt of acrylic acid and pentaerythritis polnallyl esters cross-linked copolymer are used as gelling component, phytogenous liposome suspension with included chloroform extract of medicinal plant complex is used as liposomes. Medicinal agent is produced by production of gelling agent with emulsifier, mixed with fatty components, preserving agents, added with biologically active substances and odorants. Gelling agent is made at 20-25°C, filtered, watered with mineral or mineralized water, added with glycerin, surface-active substance, emulsifier, fatty component - vegetable oil and preserving agents, heated to 60-70°C, emulsified 30-40 min, cooled to 35-40°C, added with liposome suspension, odorant and emulsified again within 30-40 min.

EFFECT: homogeneous distribution while oral rinsing and anti-inflammatory action and keratoplastic action.

5 cl, 1 ex

Description

The invention relates to dentistry, namely to means for the care of teeth, oral cavity and mouthwash.

Treatment of diseases of the oral cavity is a classic variant of the need for a complex effect, including wound healing, anti-inflammatory and bacteriostatic (bactericidal) activity. The action of anti-inflammatory elixirs, rinses and balms inhibits the growth of pathogenic microflora in the oral cavity and delays the development of the pathological process. The healing of periodontal tissues is accelerated, trophism of the gums and mucous membrane is significantly improved, and characteristic symptoms of inflammation are removed. Special substances are introduced into the dental elixirs to mineralize plaque. The combination of phytocomplexes of certain plants included in the composition of elixirs suggests the presence of various types of activity and to obtain medicinal or therapeutic agents with desired properties.

Recently, various biologically active additives (BAA) have been actively introduced into the formulation of dental elixirs, which have a regulatory effect on biochemical processes and functional disorders of the mucous membranes. Vitamins, enzymes, phosphorus and fluorine-containing substances, plant extracts, animal raw materials, beekeeping products, etc. are used as dietary supplements. Extracts of medicinal plants are of significant interest due to their low cost, availability, and a wide range of useful components contained in them.

Known means for rinsing the oral cavity, containing natural biologically active substances: water-alcohol extract of chamomile, tea tree oil, sodium fluoride, polydon, sorbitol, antiseptic and other components [1]. This elixir provides a pronounced anti-inflammatory, antioxidant, antiallergic, healing, antispasmodic, hemostatic, antiseptic and analgesic effects, and also improves metabolic processes in the tissues of the oral cavity due to the content of antioxidant vitamins (A, C, E, carotene, etc.), microelements and other natural biologically active substances (BAS). It refreshes and deodorizes the oral cavity.

However, despite the fact that this agent has a sufficient amount of biologically active substances, its water-alcohol extraction does not provide a more complete extraction of biologically active substances in comparison with chloroform, the main part of these biologically active substances is absorbed by saliva enzymes.

Known liquid hygiene products for rinsing the oral cavity in order to prevent bleeding of the gums, eliminate pain and inflammation. The drug promotes the mineralization of teeth, deodorizes the oral cavity well, providing fresh breath, contains a bioantioxidant complex obtained from the cells of relict plants - ginseng and polysacias fern leaf [2]. This bioantioxidant complex contains enzymes (enzymes) that regulate the content of peroxide radicals that have a toxic effect on cells and tissues of the body, and thereby have a therapeutic and prophylactic effect. However, together with pathogenic microflora, the drug destroys conditionally pathogenic and saprophytic strains of microorganisms, causing desensitization of the body and a decrease in tissue immunity in the oral cavity.

Known means for rinsing the oral cavity based on an aqueous extract of kelp, which contains trace elements (copper, zinc, nickel, chromium, titanium, vanadium, silver, iron, etc.), macroelements (calcium, phosphorus, sodium, potassium, etc.) derivatives of chlorophyll and carotenoids, as well as amino acids, including essential ones [3].

In general, they have remineralizing, anti-inflammatory, hemostatic, healing, active antioxidant effects, improve trophism of oral tissues and microcirculation processes. This elixir also includes a drug that dissolves dental deposits - polyvinylpyrrolidone, as well as funds that ensure deodorization and aromatization of the oral cavity.

However, this tool is characterized by the short duration of exposure to biologically active substances due to the non-liposomal form of extracts of biologically active substances of plant origin and vitamin deficiency. In addition, in the presence of metal prostheses and acrylic plastics in the patient’s mouth, the microelements included in the composition of this agent form insoluble, inactive complexes with saliva that promote allergolization of the patient’s body.

Known means for oral hygiene containing copper derivatives of chlorophyll, which are a complex compound with the porphyrin ring of chlorophyll. This leads to high biological activity, manifested in pronounced regenerative, antimicrobial, anti-inflammatory and deodorizing properties [4]. The elixir has a pleasant green color and fragrance, well refreshes the oral cavity. When using this tool, the antioxidant, antitoxic and antiallergic effect of copper derivatives of chlorophyll was noted.

However, due to the high alcohol content the patient may have a burning sensation, the drug does not affect lipid metabolism, does not have a wound healing and keratoplastic effect, which limits its use in patients with periodontitis and gingivitis.

A known tool for the prevention of periodontal disease with a bioantioxidant complex [5]. The drug has a pronounced anti-periodontal and anti-inflammatory effect, due to the high anti-radical activity of the main active component - the bioantioxidant complex isolated from plant cells of the aralia family.

Xylitol, which is part of the balm, has an anti-caries effect. The drug eliminates pain, itching and burning in the gums, prevents their swelling and bleeding, improves blood microcirculation in periodontal tissues, mineral nutrition of teeth and gums, actively relieves inflammation in diseases of the oral mucosa, freshens breath, prevents the appearance of bad breath.

However, this agent has a low concentration of biologically active substances, which does not allow it to have a long therapeutic anti-inflammatory effect on periodontal tissues, formalin, used as a preservative in the agent, creates an irritating effect, denatures proteins and epithelial enzymes and reduces the regenerative potential of the cells of the oral mucosa . The tool does not affect the lipid metabolism of the mucous membrane of the tissues of the oral cavity.

The closest in technical essence is a tool for the treatment and prevention of periodontal disease and oral mucosa, containing plant extracts, preservatives - methyl and propyl esters of paraoxybenzoic acid, perfume, water [8]. The tool relieves inflammation and promotes early healing of tissues with diseases of the oral mucosa and periodontal disease, prevents the appearance of halitosis.

However, when using this tool, an unconditional active antioxidant effect is not provided that prevents lipid peroxidation in the tissues of the oral mucosa and the formation of free radicals. In addition, there is no data confirming the prolonged effect of plant components introduced into the composition of the drug, which dictates the need for long-term use of the drug, as a result, the formation of resistant strains of microorganisms.

A thorough study of the biological and functional activity of liposomes has opened up the possibility of using their transport function, which is the delivery of biologically active substances, vitamins into the skin cells and mucous membranes, as well as the ability to regulate lipid metabolism in tissues.

When using liposomes as carriers for the targeted transport of nutrients and drugs into cells, a number of advantages are manifested: biological compatibility with the human body, the absence of allergic, toxic, pyrogenic effects of the transported components, prolonged action of the human body introduced into the skin and mucous membranes, and the absence of allergic toxic, pyrogenic effects of transported components, prolonged action introduced into cells drugs, reducing the amount of drugs introduced into the oral hygiene product while maintaining the effect of their effects, the ability to include several biologically active substances in the membrane and the internal contents of liposomes.

It is known that the high therapeutic activity of creams and pastes is leveled by their low level of penetration through the mucous membrane of the oral cavity. The optimal curative effect on the mucous membrane is possessed by an alcohol-free liposomal elixir that combines the physicochemical properties of transdermal cream and balm.

The consistent stability and penetrating ability of oral hygiene products with biologically active additives in the form of liposome preparations is determined by the technology of their preparation. The traditional technology for the preparation of liposomal elixirs and creams includes the preparation of a base, which is an oil-in-water emulsion, stabilized and brought to the required consistency by the addition of various structure-forming components and preservatives, followed by the addition of a biologically active additive and emulsification of it in the base of an elixir or cream.

This technology for obtaining creams containing liposomal components is not effective enough, since in the oil-in-water emulsion, which is free-dispersed, when phospholipid vesicles are added to it, there is no interaction between the dispersion particles. As a result, particles participate in random thermal motion, move freely under the influence of gravity. This is the reason for the instability of the drug, insufficiently effective permeability of biologically active substances into the skin and mucous membrane.

The purpose of the invention is to increase the anti-inflammatory, regenerating and antioxidant effects of the dental transdermal elixir on the mucous membrane of the oral cavity by introducing a biologically active additive into the composition, ensuring the possibility of industrial production of the product using inexpensive components and fairly simple technology.

This goal is achieved by the fact that in the transdermal elixir formulation, vegetable oil high-oleic sunflower oil of 1.8-2.0 wt.% Is used as a fat base. In vegetable oils, the content of unsaturated fatty acids is 60-90%, so the presence of a vegetable fat base increases the softening and nutritional ability of the elixir. Introduction to the formulation of vegetable high oleic oil less than 1.8 wt.% Does not provide a softening and nourishing effect, and the introduction of more than 2% of vegetable oil creates an overwhelming effect, which is contraindicated for inflamed oral mucosa.

To give the elixir colloidal stability, it is necessary and sufficient to introduce the following components in the formulation, wt.%:

Crosslinked ammonium salt acrylic acid copolymer and polyallyl ethers pentaerythritol (AKCAM) 0.8-1.0 Polyethylene glycol 1.5-2.0

The decrease in the content of AKSAM below 0.8 wt.%, PEG oleate below 1.0 wt.% Leads to a violation of colloidal stability. An increase in the content of stabilizers above the values given in the formulation, wt.%, Leads to a strong thickening of the elixir.

As a consistent additive increasing the moisture capacity of the transdermal elixir in the formulation, it is necessary and sufficient to introduce glycerol 3.5-4.0 wt.%. The glycerol content below 3.5 wt.% Or above 4.0 wt.% Does not provide the required consistency and moisture capacity of the elixir.

To impart microbiological stability to the elixir, it is necessary and sufficient to introduce the following preservatives into the elixir formulation, wt.%:

P-hydroxybenzoic acid methyl ester 0.2-0.3 P-hydroxybenzoic acid propyl ester 0.1-0.15 Paraform 0.02-0.03

A decrease in the content of preservatives (paraform, nipagin and nipazole) leads to a violation of microbiological stability during storage. An increase in the content of preservatives can cause irritation of the mucous membrane, and also adversely affect the structure of the liposomal suspension.

Introduction to the formulation of a suspension of liposomes of 20 wt.% Provides an effective effect on the inflamed mucosa of biologically active components isolated during chloroform extraction from a mixture of medicinal herbs. A decrease in the content of liposomal suspension does not ensure the delivery of the required amount of biologically active substances to the epithelial cell of the oral mucosa. The increase in liposome content does not give a pronounced therapeutic effect, and is also not economically feasible.

To give the elixir a pleasant smell, a flavoring agent of 0.2-0.4 wt.% Was introduced into the formulation. Introduction below 0.2 wt.% Does not provide the desired tone of the smell, the introduction of above 0.4 wt.% Perfumes creates a pungent odor. The introduction of mineral or mineralized water into the formulation makes it possible to expand the spectrum of trace elements.

The inventive method for producing a dental transdermal elixir includes preparing an aqueous emulsion of a gelling component - a copolymer of acrylic acid and polyallyl pentaerythritol esters at 20-25 ° C, filtering the emulsion, diluting with mineral or mineralized water in the ratio with distilled water 50%: 50% and adding glycerol, emulsifier - polyethylene glycol, fatty base - vegetable oil and preservatives - methyl ether of paraoxybenzoic acid and propyl ether of paraoxybenzoic acid, heating tion mixture to 60-70 ° C and emulsification for 30-40 min, followed by cooling the emulsion to 35-40 ° C, adding a suspension of liposomes, perfumes, emulsifying within 30-40 min. A causal relationship of the distinctive features of the composition and method of producing a transdermal elixir for the treatment and prevention of oral diseases with the achievement of a technical result is manifested in the following.

To ensure the wound healing and anti-inflammatory activity of the elixir, an extract of the phytocomplex of medicinal herbs was used - large plantain, sweet clover, marigold, St. John's wort, chamomile, medicinal sage, dioecious nettle, aloe vera juice, sea buckthorn oil in combination with a natural fruit extract - hawthorn.

Introduction to the formulation as a biologically active additive of a 20 wt.% Suspension of vegetable liposomes with the chloroform extract of the phytocomplex of medicinal herbs included — the large plantain, Melilotus officinalis, drug marigold, St. John's wort, chamomile, medicinal sage, dioecious nettle, tree aloe juice , sea buckthorn oil provides an increase in anti-inflammatory, regenerating, vitaminizing properties of the product.

The inclusion of a bioflavonoid antioxidant, an extract of the fruits and flowers of hawthorn, provides an active antioxidant effect that prevents lipid peroxidation in the tissues of the oral mucosa.

The increased active principle of a biologically active additive of the claimed invention in comparison with known analogues is due to a number of factors. The combined use of plant extracts makes it possible to construct liposomes from the highest possible qualitative composition of phospho- and glycolipids. The chloroform extraction of phyto-collection allows to extract not only vitamins A, E, K, PP, B, unsaturated fatty acids, but also phytoglycolipids. Other well-known methods for the extraction of biologically active substances (aqueous, salt, alcohol, carbon-containing) do not provide sufficient, complete extraction of lipid components, therefore, cannot be used to obtain the substances necessary for the claimed elixir [6, 7].

The use of chloroform extracts of hawthorn fruits, chamomile, nettle, plantain, St. John's wort, sage, aloe juice, sea buckthorn oil allows you to extract a complex of biologically active components to give the elixir the required properties, and the interaction of all components provides a powerful synergistic effect. The anti-inflammatory and disinfecting effect is achieved thanks to azulene in combination with sesquiterpenoids contained in the extract of St. John's wort, plantain, chamomile, nettle, and sage. The action of azulenes and sesquiterpenoids is enhanced by the tannins of the paracatechin series contained in extracts of nettle, sage and chamomile. Anthracene derivatives contained in aloe juice and St. John's wort extract have bactericidal and biostimulating, as well as powerful antimicrobial effects. Carotenoids, vitamins A, PP, K, B vitamins (hawthorn, sea buckthorn, chamomile, sage, St. John's wort, nettle) have an epithelizing, healing, fortifying effect on the mucosa. The presence of vitamin A and E in the extract of hawthorn fruit in combination with nettles and St. John's wort tannins provides a sufficient antioxidant effect, which ensures inhibition of peroxide reactions and the formation of free radicals.

The use of mineral or mineralized water with a high content of trace elements in the formulation of the invention allows to intensify the synthesis of collagen of connective tissue, saturation of cells with essential trace elements inhibits inflammatory reactions, stimulates regeneration processes in the epithelial cells of the oral mucosa. The possibility of obtaining a dental transdermal elixir is illustrated by a specific embodiment.

Example 1. Mineral or mineralized water is poured into the mixer (water corresponds to SanPin 2.3.2 560-96 p. 6.8.1.2.) Based on the calculation of filling the apparatus volume by 70% and with the stirrer turned on, add AKSAM (ammonium salt of a rare crosslinked copolymer of acrylic acid and polyallyl pentaerythritol esters, TU 301-02-143-90) at the rate of 10 g of AKSAM per 1 liter of solution. The mixture is stirred at 20-25 ° C for 20-30 minutes. The resulting jelly-like mass is passed through a sedimentary strainer. In the reactor, the jelly-like mass is diluted with distilled water to 1% AKSAM and with a stirrer operating at a speed of 60 rpm, glycerin (GOST 6824-76) is added at the rate of 4.0% of the total volume of finished products, PEG-400 oleate (polyethylene glycol, TU 18 -16-94-82), high oleic vegetable oil at the rate of 2.0% of the total volume of the finished product and paraforms (TU 6-05-930-78) at the rate of 0.03% of the total volume of the finished product, paraoxybenzoic acid methyl ester (TU 18-16-386-81) at the rate of 0.3% and propyl ester of paraoxybenzoic acid (TU 18-16-387-81) at the rate of 0.1% of the total volume of finished products. The mixture is heated in the reactor to 60-70 ° C and stirred for 30-40 minutes. Then the mixture is cooled to 40-45 ° C and a suspension of liposomes containing the organic extract of the phytocomplex at the rate of 20% suspension of the total volume of the finished product is slowly poured into the reaction mass, fragrance (TU 10-04-16-39-89) is added at the rate of 0 , 2% to the total volume of the finished product.

The resulting mass is stirred for 30-40 minutes, cooling it to 30 ° C, and sent for filtration and packaging.

The organic extract of the phytocomplex is prepared as follows. Dried and ground medicinal herbs, including psyllium plantain, medicinal sweet clover, calendula drugstore, St. John's wort perforated, chamomile, medicinal sage, dioica nettle, as well as aloe juice and tree buckthorn oil, taken in the ratio 1: 1: 1: 2: 2: 1 : 1: 1: 2, in combination with a biocomplex of a natural antioxidant - extract of fruits and flowers of hawthorn in a ratio of 1: 2, kept under a bactericidal lamp for 3 hours. Then the mixture of herbs is poured with chloroform in a ratio of 1:20, the suspension is stirred and insisted with stirring in a dark place for 9-14 days. At the end of the extraction, the suspension is defended and the supernatant is separated.

A suspension of liposomes of plant origin is prepared by the reverse phase method. The claimed content of all constituent components in the formulation of the transdermal elixir optimally ensures the achievement of the desired effect. An experimental batch of the claimed dental transdermal elixir was tested at the Department of Dentistry of the FPO and the Pyatigorsk State Pharmaceutical Academy at the Stavropol State Medical Academy in order to assess the irritating and allergenic effects, effects on the liver and morphological structure of the mucous epithelium. Experimental clinical trials were conducted on 79 volunteers aged 18 to 35 years and on laboratory animals.

The results of experimental studies showed that the dental transdermal elixir with prolonged use for 30 days did not have a general toxic, irritating and allergenic effect. The results of morphological studies in experimental animals indicate the absence of pathological changes in the structure of the epidermis, dermis, mucous membranes and liver. The hydrogen index of the dental elixir is 7.4 with acceptable standards of 4.5-9.0. Hygiene for dental and oral care - the dental elixir has a pleasant smell, delicate and uniform consistency, mixes well with saliva, quickly and steadily envelops the mucous membrane of the oral cavity, providing a calming and keratoplastic effect on the tissues of the mucosa and periodontium.

The possibility of practical use of the claimed formulation of a dental transdermal elixir is illustrated by a specific example. This technical result is confirmed by the results of clinical trials in 79 volunteers aged 18 to 35 years with symptoms of hypertrophic gingivitis, periodontitis 1 and 2 degrees, bleeding gums.

1. When using a dental elixir, there is a positive anti-inflammatory effect on the Mulleman bleeding index (1971), which is 1.23 ± 0.42 and 0.59 ± 0.29 at the examination time of 14 and 28 days, respectively.

2. When using the developed dental elixir, an improvement in the hygienic condition of the oral cavity is noted, which is confirmed by a decrease in the Silnes-Low index by an average of 45.8% compared with the initial state.

3. When using the developed dental elixir, the most pronounced decrease (2.3 times) in the smear content of all types of bacteria was noted compared with the control groups. The frequency of occurrence of Candida spp. During the observation periods of 1, 3, 7, and 14 days decreased after the application of the developed elixir by an average of 15.4%, amounting to 12.3% in the period of 28 days, which indicates the stabilization of the phenomenon of dysbiosis in the oral cavity.

The use of the claimed composition of the transdermal dental elixir will allow the mass production of inexpensive and effective hygiene products for the care of teeth and oral cavity of domestic production.

Information sources

1. RF patent No. 2160585, A 61Q 11/00.

2. RF patent No. 2095052.

3. RF patent No. 1811400.

4. RF patent No. 2005464.

5. RF patent No. 2095052.

6. RF patent №2020944, А61К 35/10.

7. RF patent No. 2040265, A61K 35/78.

8. RF patent No. 2005466.

Claims (6)

1. Dental transdermal elixir containing a gel-forming component, preservatives - methyl and propyl esters of paraoxybenzoic acid, glycerin, biologically active extracts of plant origin, liposomes, perfume, water, characterized in that it additionally contains surfactants, vegetable oil, paraform, emulsifier - polyethylene glycol wherein, as the gelling component, an ammonium salt of a rare crosslinked copolymer of acrylic acid and polyallyl pentaerythritol esters is used, and a suspension of liposomes is used as liposomes plant origin in the following components, wt.%: vegetable oil 1.8-2.0 cosmetic glycerin 3,5-3,9 paraoxybenzoic acid methyl ester 0.2-0.3 paraoxybenzoic acid propyl ester 0.1-0.14 paraform 0.02-0.03 liposome suspension containing extracts plant origin 8.0-22.0 perfume 0.2-0.5 anionic surfactant 0.5-2.0 ammonium salt of a crosslinked copolymer acrylic acid and polyallyl pentaerythritol esters 0.7-1.0 polyethylene glycol 1.5-2.0 water up to 100 2. The dental elixir according to claim 1, characterized in that it contains up to 20 wt.% Suspension of liposomes of plant origin. 3. The dental elixir according to claim 1, characterized in that it contains 0.5-1.5 wt% lauryl sulfate as an anionic surfactant. 4. A dental elixir according to claims 1 and 2, characterized in that the liposome suspension contains a phytocomplex of medicinal herbs of chamomile, St. John’s wort, large plantain, honey clover, calendula, medicinal sage, nettle, and sea-tree and sea-buckthorn oil in combination with a biocomplex of natural antioxidant - extract of fruits and flowers of hawthorn. 5. The dental elixir according to claim 1, characterized in that distilled or mineral or mineralized water is used as water. 6. A method of obtaining a dental elixir, including the preparation of a gelling component - a copolymer of acrylic acid and polyallyl esters of pentaerythritol with an emulsifier, mixing it with fat components, preservatives, emulsifiers, adding a biologically active substance, a surfactant and perfumes, characterized in that the gelling component prepared at 20-25 ° C, then filtered, diluted with mineral or mineralized water and glycerin added, emulsifier - polyethylene glycol, fat component - Testing oil and preservatives - paraoxybenzoic acid methyl ester, paraoxybenzoic acid propyl ester, paraform, the mixture is heated to 60-70 ° C, emulsified for 30-40 minutes, cooled to 35-40 ° C, a suspension of liposomes, perfume are added and again emulsified within 30-40 minutes