RU2487698C1 - Nonabrasive toothpaste containing enzyme papain, harpagophytum extract d,l-pyrrolidone carboxylate n-cocoyl ethylarginate and sodium fluoride - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: present invention refers to dentistry, namely to oral care products. The presented nonabrasive toothpaste contains the enzyme papain, harpagophytum extract, D,L-pyrrolidone carboxylate N-cocoyl ethylarginate and sodium fluoride, as well as a carrier - sodium carboxymethyl cellulose, an emulsifier, a preserving agent, a flavouring agent, sorbitol 70% and dimeralised water in certain proportions. Using the toothpaste for oral care cleansing enables reducing plaque formation on the dental surface with no abrasive materials to be used by enzymatic plaque destruction.

EFFECT: toothpaste possesses manifested cleansing, anti-inflammatory and haemostatic action.

9 tbl, 2 ex

Description

The present invention relates to dentistry, namely to a non-abrasive toothpaste for cleaning the oral cavity containing the following components: papain, harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate and sodium fluoride, sodium carboxymethyl cellulose, emulsifier, preservative, flavoring agent, sorbitol 70, sorbitol %, demineralized water.

The invention allows to reduce without the use of abrasive materials, such as calcium carbonate, calcium pyrophosphate, dicalcium phosphate, silicon dioxide, aluminum hydroxide, the formation of plaque on the surface of the teeth by 70% due to the enzymatic destruction of plaque, remineralization of tooth enamel and the destruction of pathogenic microflora, reduce inflammation in the oral cavity by 90%. Toothpaste does not contain abrasive components and has good organoleptic properties: it is white in color, with a pleasant smell and good taste.

The invention relates to medicine, namely to dentistry.

There are various therapeutic and prophylactic toothpastes used for the prevention of inflammatory periodontal diseases, containing anti-caries and anti-inflammatory components that are not enzymes, for example, sodium fluoride, extracts of medicinal plants and vitamins (Medical and preventive toothpaste "Silca Herb plus" (Germany), Tea tree oil Toothpaste "Natural whitening toothpaste with tea tree oil" (USA). However, this paste has a low cleaning ability, because it does not contain components that dissolve directionally slaughter.

Known toothpaste with an enzyme-containing composition, where the enzyme is selected from the group of proteinases including papain (Rembrandt Whitening Toothpaste (USA), as well as a paste containing lysozyme, glucose oxidase, lactoperoxidase and lactoferrin (Biotene toothpaste ( Finland), which is used to treat xerostomia, the described toothpaste does not contain D, L-pyrrolidone carboxylate n-cocoyl ethylarginate, which has the ability to normalize the microflora of the oral cavity, and therefore cannot be used to control pathogenic micro flora.

From RU 2355420, publ. 05/20/2009 (examples, claims) Known toothpaste, including: the abrasive component is silicon dioxide, lactulose - 2.0-6.0 wt.%, A combination of enzymes: papain - 0.2-1.0 wt.% And lysozyme 0.01-0.4 wt.%. Toothpaste also contains: sodium carboxymethyl cellulose - 0.5-0.7 wt.%, Preservatives (sodium methylparaben and sodium propylparpaben) in a total amount of 0.2-0.8 wt.%, Sodium lauryl sulfate and sodium lauroyl sarcosinate in total - 0.6-3.0 wt.%, Flavoring - 0.05-2.0 wt.% And demineralized water. In RU 2355420, publ. 05/20/2009 (examples, claims) it is also indicated that the introduction of lactulose in the composition of the toothpaste helps to restore the natural microflora of the oral cavity.

From US 4150113, publ. 04/17/1979 (the entire document, in particular column 5 of the description, examples, claims), dentifrices are known, including toothpastes, mouthwashes, chewable tablets and gums, the main active ingredient of which is glucose oxidase. It is indicated that in addition to glucose oxidase, it is advisable to include carbohydrase, for example, alpha-amylase, glucoamylase (amyloglucosidase), dextranase, and invertase.

From US 4578265, publ. 03/25/1986 (examples, claims) a dentifrice with antibacterial properties is known, including glucose oxidase, lactoperoxidase and potassium or ammonium thiocyanate.

However, these agents do not contain proteases, in particular papain.

From RU 2333768, publ. September 20, 2008 (see the Enzymes section), it is also known that it is advisable to include carbonic anhydrases such as glucoamylase, alphaamylase, dextranase, and proteases such as papain in the composition for caring for the oral cavity. Moreover, this combination of enzymes can be supplemented with lysozyme. However, these compositions do not contain D, L-pyrrolidone carboxylate N-cocoyl ethylarginate.

Toothpastes containing the papain enzyme; harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate and sodium fluoride for topical use to restore the oral microflora and prevent inflammatory periodontal diseases are not described.

Thus, it is an object of the present invention to provide a toothpaste containing the papain enzyme; harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate, sodium fluoride and not containing abrasive components, which can be used to restore oral microflora and prevent inflammatory periodontal diseases caused by cariogenic microorganisms such as S. mutans, S. aureus and others.

According to the present invention, there is provided a toothpaste containing as active ingredients: 0.01-5.0 wt.% Papain, 0.01-5.0 wt.% Harpagophytum extract, 0.01-5.0 wt.%, D L-pyrrolidone carboxylate N-cocoyl ethylarginate; 0.05-0.26 wt.% Sodium fluoride and cosmetically acceptable carriers or excipients.

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

Papain 0.01-5.00 Harpagophytum Extract 0.01-5.00 D, L-pyrrolidone carboxylate N-cocoyl ethylarginate 0.01-5.00 Sodium Fluoride 0.05-0.26 Sodium carboxymethyl cellulose 0.50-0.70 Emulsifier 0.01-5.00 Preservative 0.01-1.00 Flavoring 0.01-1.00 Sorbitol 70% 30.00-40.00 Demineralized water 57.04-69.31

The active ingredient of the claimed non-abrasive paste are: papain, harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate and sodium fluoride. Papain is capable of breaking peptide bonds from sulfur-containing amino acid residues. D, L-pyrrolidone carboxylate N-cocoyl ethylarginate and sodium fluoride during the preparation of the composition, interacting with each other during the exchange reaction form D, L-pyrrolidone carboxylate sodium and fluoride N-cocoyl ethyl arginate. D, L-pyrrolidone carboxylate sodium has a moisturizing effect on the oral mucosa, preventing xerostomia. During toothbrushing, N-cocoyl ethylarginate fluoride forms a stable layer on the enamel surface that inhibits the development of pathogenic microflora and simultaneously deposits fluoride ions, contributing to the slow remineralization of tooth enamel. Harpagophytum extract eliminates inflammation in the oral cavity.

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, the creation of a fluoride depot and a mild antiseptic on the surface of the teeth, with the aim of antimicrobial and anticaries protection against exposure to pathogenic microorganisms. For the preparation of non-abrasive pastes, the following substances are used: Papain, Harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate, Sodium fluoride. Papain is obtained from papaya fruits by extraction from crushed raw materials, followed by purification and freeze drying. 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. Harpagophytum extract is used to treat various inflammatory diseases. D, L-pyrrolidone carboxylate N-cocoyl ethylarginate is used as a preservative.

The non-abrasive paste of the present 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.

Additional advantages of this composition are the ability to restore the natural microflora of the oral cavity.

The proposed non-abrasive paste reduces plaque formation by 70% and is completely harmless and safe for prolonged use.

The significant differences of the proposed non-abrasive paste are as follows.

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

The activity of the claimed composition is due to the activity of its constituent enzymes. It was found that a topical cosmetic composition containing as active ingredients: 0.01-5.0 wt.% Papain, 0.01-5.0 wt.% Harpagophytum extract, 0.01-5.0 wt.% , D, L-pyrrolidone carboxylate N-cocoyl ethylarginate; 0.05-0.26 wt.% Sodium fluoride and cosmetically acceptable carriers or excipients are stable in relation to the activity of the enzyme 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

A cosmetic composition in the form of a non-abrasive paste based on papain, harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate, sodium fluoride and cosmetically acceptable carriers or excipients has the following composition:

Papain 0.01 Harpagophytum Extract 0.01 D, L-pyrrolidone carboxylate N-cocoyl ethylarginate 0.01 Sodium Fluoride 0.05 Sodium carboxymethyl cellulose 0.50 Emulsifier 0.01 Preservative 0.01 Flavoring 0.01 Sorbitol 70% 30.08 Demineralized water 69.31

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

EXAMPLE 2

A cosmetic composition in the form of a non-abrasive paste based on papain, harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate, sodium fluoride and cosmetically acceptable carriers or excipients has the following composition:

Papain 0.25 Harpagophytum Extract 0.25 D.L-pyrrolidone carboxylate N-cocoyl ethylarginate 0.25 Sodium Fluoride 0.26 Sodium carboxymethyl cellulose 0.70 Emulsifier 0.25 Preservative 0.50 Flavoring 0.50 Sorbitol 70% 40.00 Demineralized water 57.04

The specified composition is prepared as in EXAMPLE 1.

Evaluation of the stability of enzymes in topical compositions

Since the main disadvantage of enzymes is their instability during long-term storage of finished forms based on them during the shelf life, a comparative assessment was made of the preservation of the activity of the enzyme during storage in the form of a solution and in the form of a composition for local use.

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 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.

To quantify papain, the Lowry method was used. The determination method is based on the fact that proteins with copper salts in an alkaline medium restore Follin's reagent. A Coomassie G-250 dye solution was prepared as follows: 100 mg of the dye was dissolved in 100 ml of phosphoric acid, diluted with water 5 times, then filtered through a thick paper filter. To determine the concentration in the sample, an equal volume of dye was added, mixed and the absorbance of the solution was measured at a wavelength of 595 nm.

The results are shown in the following table.

Table 1 Test samples Main ingredients Storage stability one 2 3 Pasta No. 1 According to Example 1 Activity 95% for papain within 1 year of observation Pasta No. 2 According to Example 2 Activity 82% for papain within 1 year of observation Native enzyme solution - 10% activity for papain for 7 days

As can be seen from the table 1, the introduction of enzymes in the composition for local use allows you to get stable cosmetic compositions for local 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 D, L-pyrrolidone carboxylate N-cocoyl ethylarginate was determined by serial dilution. 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, and Esherichia coli were grown in test tubes in a medium with meat and peptone broth at 37 ° C for 24 hours, and a Candida albicans culture on Saburo agarized seldure 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.

table 2 Name of ingredient Staphylococcus aureus Bacillus cereus Esherichia coli Candida albicans MIC, mg / ml MCC, mg / ml MIC, mg / ml MCC, mg / ml MIC, mg / ml MCC, mg / ml MIC, mg / ml MCC, mg / ml D.L-pyrrolidone carboxylate N-cocoyl ethylarginate 5 10 5 10 5 10 one twenty

As can be seen from table 2, the optimal inhibitory concentration is: for D, L-pyrrolidone carboxylate N-cocoyl ethylarginate: 5 mg / ml in the case of Staphylococcus aureus, Bacillus cereus, Escherichia coli; 1 mg / ml - for Candida albicans; bactericidal concentration for D, L-pyrrolidone carboxylate N-cocoyl ethylarginate - 10 mg / ml in the case of Staphylococcus aureus, Bacillus cereus, Escherichia coli; 20 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 28-1 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 indicator of the hygiene index for all teeth in which the index indicators were 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:

Cleaning efficiency = [(IG _do1 - IG _doX ) / IG _do1 ] × 100, where

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

IG _doX is an indicator of the hygiene index obtained during a subsequent examination (7, 14, 21, 28 days of 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 (1, 7.14, 21, 28 days);

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

From table 3, 4 and 5 it can be seen that the proposed toothpaste has an increased cleaning ability, and therefore anti-caries effect due to a more pronounced removal of dental plaque and provides the removal of 62.22% 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 - 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 = [(PMA ₁ - PMA _X ) / PMA ₁ ] × 100,

Where

PMA ₁ - an indicator of the PMA index obtained at the initial examination on the 1st day of the study;

RMA _X - an indicator of the RMA index obtained during a subsequent examination (7, 14, 21 and 28 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 probans disappeared from the phenomenon of catarrhal gingivitis, and the PMA index decreased from 49.5 to 9.4, which corresponded to 81 , 01% anti-inflammatory efficacy 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 effectiveness = [(IR ₁ - IR _X ) / IR ₁ ] × 100, where

IK ₁ - bleeding index at the beginning of the study;

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

The data are given in Tables 8 and 9. It can be seen from them that after using this paste, the condition of periodontal tissues improves, and the bleeding of the gums decreases from 2.5 to 0.9 points, which corresponds to 64.00% of the hemostatic effectiveness of this paste.

Thus, the proposed toothpaste has a higher cleansing (62.22% cleansing effectiveness), anti-inflammatory (81.01% anti-inflammatory effect) and hemostatic (64.00% hemostatic effectiveness) effect.

Tab. 3 condition OHI-S Green-Vermillion 1st day 7th day 14th day 21st day 28th day Before cleaning 2.7 2,3 1,5 1,2 1,02 After cleaning 1,5 1.4 1,2 0.97 0.90 Tab. four Reduction. plaque with a single use of toothpaste 1st day 7th day 14th day 21st day 28th day 44.44% 35.22% 20.00% 19.17% 11.76% Tab. 5 The cleaning effectiveness of the paste (compared with the 1st day) 7th day 14th day 21st day 28th day 14.81% 44.44% 55.56% 62.22% Tab. 6 RMA Index 1st day 7th day 14th day 21st day 28th day 49.5% 35.7% 25.6% 19.3% 9.4% Tab. 7 Anti-inflammatory efficacy 7th day 14th day 21st day 28th day 27.88% 48.28% 61.01% 81.01% Tab. 8 Kechka bleeding index 1st day 7th day 14th day 21st day 28th day 2,5 2.2 1.8 1,6 0.9 Tab. 9 Hemostatic effectiveness 7th day 14th day 21st day 28th day 12.50% 28.00% 36.00% 64.00%

Claims (1)

Non-abrasive toothpaste containing enzyme preparations, a polymeric carrier, water, preservative, emulsifier and other acceptable excipients, characterized in that it contains: papain, harpagophytum extract, D, L-pyrrolidone carboxylate N-cocoyl ethylarginate, sodium fluoride, as a carrier - sodium carboxymethyl cellulose, emulsifier, preservative, flavor, sorbitol 70%, demineralized water in the following ratio, wt.%:
papain 0.01-5.00 harpagophytum extract 0.01-5.00 D, L-pyrrolidone carboxylate N-cocoyl ethylarginate 0.01-5.00 sodium fluoride 0.05-0.26 sodium carboxymethyl cellulose 0.50-0.70 emulsifier 0.01-5.00 preservative 0.01-1.00 flavor 0.01-1.00 sorbitol 70% 30.00-40.00 demineralized water 57.04-69.31