RU2482835C2 - Product for oral cavity care and methods of its application and manufacturing - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to composition for oral cavity care and methods of its application. Claimed is composition for oral cavity care, which contains: arginine, in free form or in form of salt in amount from 0.1 to 20 wt % of total composition weight; triclosan in amount from 0.01 to 5 wt % of total composition weight; anionic polymer, which is a copolymer of methyl vinyl ether and maleic anhydrate; anionic surfactant in amount from 0.01 to 10 wt % of total composition weight; soluble fluoride salt in amount from 0.01 to 2 wt % of total body weight, in order to provide 50-25000 ppm of weight of fluoride ions, in which soluble fluoride salt or source of fluoride ions is selected from sodium fluoride, sodium monofluorophosphate and their mixtures; and abrasive material, which contains fraction of minor particles, constituting at least about 5 wt % of total composition weight, and in said fraction minor particles have average diameter d50 smaller than 5 mcm.

EFFECT: application of composition for oral cavity care along with improved delivery of antibacterial agent provides additional advantages in acceleration of remineralisation and restoration of precarious affection foci due to combination of fluoride and arginine, as well as due to application of finely disperse abrasive as composition component.

11 cl, 1 tbl, 7 ex

Description

This application claims the priority of the following applications: US application No. 61/027431, filed February 8, 2008, US application No. 61/027432, filed February 8, 2008, and US application No. 61/027420, filed February 8, 2008, the contents of which are included the present invention by reference.

FIELD OF THE INVENTION

The present invention relates to oral care compositions containing a basic amino acid in free or salt form and an antibacterial agent, for example triclosan, and to methods for using and creating said compositions.

BACKGROUND OF THE INVENTION

In order to care for the oral cavity, arginine and other basic amino acids have been proposed, which are considered to be largely effective against cavity formation and tooth sensitivity. At the same time, it was confirmed that the combination of these basic amino acids with minerals effective for caring for the oral cavity, for example, with fluoride and calcium, is a difficult task when creating a product for caring for the oral cavity with acceptable long-term stability. In particular, the basic amino acid can raise the pH and promote the dissociation of calcium ions, which can react with fluoride ions to form an insoluble precipitate. In addition, a higher pH can cause irritation. However, a system for utilizing arginine bicarbonate (which is preferred according to the prior art) at a neutral or acidic pH can release carbon dioxide, which leads to bloating and rupture of containers. In addition, it can be expected that when the pH level decreases to a neutral or acidic reaction, the effectiveness of the formulation will decrease, since arginine can form an insoluble arginine-calcium complex, which has a weaker affinity for the tooth surface, and, in addition, a decrease in pH will reduce any possible buffering effect of the formulation against the cariogenic effect of lactic acid in the oral cavity. Partly due to such non-specific formulation problems, and partly because arginine was generally regarded as a potential alternative to fluoride in the art and not as a co-acting agent, there was little motivation to make oral care products containing arginine and fluoride. Additional barriers potentially included the addition of an antibacterial agent. For example, a commercially available arginine-based toothpaste, such as ProClude® and DenClude®, contains arginine bicarbonate and calcium carbonate, but does not contain fluoride or any antibacterial agent.

At the same time, many dentists recognize the importance of antibacterial agents, such as triclosan, in toothpaste. At the same time, there is the problem of delivering an effective amount of these agents to the teeth and gums, and their solubility, delivery and retention on the teeth depends on the formulation. For example, triclosan (5-chloro-2- (2,4-dichlorophenoxy) phenol) is slightly soluble in water.

Thus, there is a need for a stable oral care product that contains a basic amino acid and at the same time contains minerals having beneficial effects, such as fluoride and calcium, as well as a need for a product with improved delivery of antibacterial agents.

SUMMARY OF THE INVENTION

It has now been unexpectedly discovered that a basic amino acid, such as arginine, can significantly increase the solubility, delivery, retention and effectiveness of an antibacterial agent, such as triclosan, against bacteria.

Thus, the present invention encompasses compositions for caring for the oral cavity and methods for their use that effectively inhibit or reduce plaque formation, reduce the number of acid-producing bacteria (cariogenic) that have the effect of remineralizing the teeth and inhibit or reduce the development of gingivitis. The present invention also encompasses compositions and methods for cleaning the oral cavity and improved methods for enhancing oral health and / or overall health of the body, including cardiovascular health, for example, by reducing the possibility of systemic infection through the tissues of the oral cavity.

Thus, the present invention relates to a composition for caring for the oral cavity (composition according to the invention), for example, to a toothpaste containing:

(i) an effective amount of a basic amino acid in free or salt form, for example arginine;

(ii) an effective amount of an antibacterial agent, for example triclosan.

Optionally, the present invention further comprises an anionic surfactant, for example sodium lauryl sulfate; an effective amount of a fluoride source, for example, a soluble fluoride salt; and / or an anionic polymer, for example a copolymer of methyl vinyl ether and maleic anhydride. Thus, in one embodiment, the invention relates to a toothpaste containing an arginine salt, for example arginine hydrochloride, arginine phosphate or arginine bicarbonate; triclosan; anionic surfactant, for example sodium lauryl sulfate; soluble fluoride salt, for example sodium monofluorophosphate or sodium fluoride.

In one embodiment, the invention relates to a composition according to the invention (composition 1.1), optionally containing particles, to a composition having an RDA (abrasive wear of dentin by radioactive method) of less than about 200, for example less than about 160, for example from about 40 to about 140, for example, containing at least about 5%, for example at least about 20% of particles having an average diameter d50 of less than about 5 micrometers, for example silica particles having a d50 of about 3 to about 4 micrometers, or precipitated carbonate to alcium having a d50 of from about 0.5 to about 3 micrometers.

In specific embodiments, the compositions of the invention are toothpaste containing additional components selected from one or more components: water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, moisturizing agents, thickeners, antimicrobial agents, preservatives, flavorings , colorants and / or combinations thereof.

Without reference to a specific theory, it is assumed that a significant factor in the beneficial effect of arginine is the ability to assimilate arginine and other essential amino acids by certain types of bacteria, for example S. sanguis, which are not cariogenic and compete for location on the teeth and oral cavity with cariogenic bacteria, such as S. mutans. Arginolytic bacteria can use arginine and other basic amino acids to produce ammonia, thereby raising the pH of their environment, while cariogenic bacteria metabolize sugar to produce lactic acid, which tends to lower plaque pH and tooth demineralization, which ultimately leads to the formation of cavities. It is believed that the regular use for a long time of the composition according to the invention will lead to a relative increase in arginolytic bacteria and a relative decrease in the number of cariogenic bacteria, resulting in an increase in the pH level of plaque, tooth resistance to cariogenic bacteria and their harmful effects will be formed. It is assumed that this effect of increasing the pH level can be mechanically separated from the action of fluoride and can complement the action of fluoride to accelerate remineralization and strengthen tooth enamel.

However, regardless of the exact mechanism of action, it was unexpectedly found that the combination of fluoride and a basic amino acid, for example arginine, in an oral care product according to particular embodiments of the present invention provides unexpected additional benefits in accelerating remineralization, restoring precarious lesions and strengthening oral health, which are qualitatively different from the effect that can be observed when applying compositions containing effective to lichestvo any of the compounds individually. In addition, it was found that this effect can be further enhanced by the addition of finely divided abrasive, the action of which can contribute to the filling of microcracks in enamel and microchannels in dentin.

It has also been unexpectedly discovered that the presence of a basic amino acid reduces the adhesion of bacteria to the tooth surface, especially in the case of a combination of a basic amino acid with an anionic surfactant.

Of particular importance to the present invention is that the basic amino acid significantly increases the solubilization, release, delivery, deposition and effectiveness of antibacterial agents such as triclosan.

Thus, the present invention further relates to methods of (i) reducing or preventing the formation of dental caries, (ii) reducing, repairing or preventing early damage to the enamel, for example, detected by quantitative light fluorescence (QLF) or electrometric method for determining caries (ECM), ( iii) reduce or prevent demineralization and accelerate remineralization of teeth, (iv) reduce tooth sensitivity, (v) reduce or prevent gingivitis, (vi) promote ulcer healing and wounds in the oral cavity, (vii) reducing the number of bacteria producing acid, (viii) increasing the relative content of arginolytic bacteria, (ix) preventing the formation of microbial biofilms in the oral cavity, (x) increasing and / or maintaining a pH of plaque after sugar loading at least at pH 5.5, (xi) reducing plaque formation, (xii) treating, alleviating or reducing dry mouth syndrome; (xiii) strengthening overall health, including cardiovascular health, for example, by reducing the possibility of general infection through the tissues of the oral cavity, (xiv) reducing erosion of the teeth, (xv) whitening teeth, (xvi) building resilience or protecting teeth against cariogenic bacteria and / or (xvii) cleansing the teeth and oral cavity, which contain the use of the composition of the invention in the oral cavity, for example, the use of the composition of the invention in the oral cavity of a patient in need of such use.

DETAILED DESCRIPTION OF THE INVENTION

Thus, the present invention contains a composition for caring for the oral cavity (composition 1.0), containing

(i) an effective amount of a basic amino acid, for example arginine, in free form or in salt form;

(ii) an effective amount of an antibacterial agent, for example triclosan; and

(iii) optionally an anionic surfactant, for example sodium lauryl sulfate; an effective amount of a fluoride source, for example, a soluble fluoride salt; and / or an anionic polymer, for example a copolymer of methyl vinyl ether and maleic anhydride;

for example, any of the following compositions.

1.0.1. Composition 1.0, in which the basic amino acid is arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminopropionic acid, their salts and / or combinations thereof.

1.0.2. Composition 1.0 or 1.0.1, in which the basic amino acid has an L-configuration.

1.0.3. Any of the preceding compositions presented in the form of a salt of a di or tripeptide containing a basic amino acid.

1.0.4. Any of the preceding compositions in which the main amino acid is arginine.

1.0.5. Any of the previous compositions in which the main amino acid is L-arginine.

1.0.6. Any of the preceding compositions in which the basic amino acid is partially or fully present in salt form.

1.0.7. Composition 1.0.6, in which the main amino acid is arginine phosphate.

1.0.8. Composition 1.0.6, in which the basic amino acid is in the form of arginine hydrochloride.

1.0.9. Composition 1.0.6, in which the main amino acid is arginine sulfate.

1.0.10. Composition 1.0.6, in which the main amino acid is arginine bicarbonate.

1.0.11. Any of the preceding compositions in which a salt of a basic amino acid is formed in an in situ formulation by neutralizing the basic amino acid with an acid or acid salt.

1.0.12. Any of the preceding compositions in which a salt of a basic amino acid is formed by neutralizing a basic amino acid to form a premix before combining with a fluoride salt.

1.0.13. Any of the previous compositions in which the basic amino acid is present in such an amount that its weight corresponds to from about 0.1 to about 20%, for example from about 1% to about 10%, of the total weight of the composition, while the weight of the basic amino acid is calculated by weight free base forms.

1.0.14. Composition 1.0.11, in which the basic amino acid is present in an amount of about 7.5% by weight of the total weight of the composition.

1.0.15. Composition 1.0.11, in which the basic amino acid is present in an amount of about 5% by weight of the total weight of the composition.

1.0.16. Composition 1.0.11, in which the basic amino acid is present in an amount of about 3.75% by weight of the total weight of the composition.

1.0.17. Composition 1.0.11, in which the basic amino acid is present in an amount of about 1.5% by weight of the total weight of the composition.

1.0.18. Any of the preceding compositions in which the fluoride salt is selected from tin fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g., N'-octadecyl trimethylenediamine-N, N, N'-tris (2- ethanol) -dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.

1.0.19. Any of the preceding compositions in which the fluoride salt is fluorophosphate.

1.0.20. Any of the preceding compositions in which the fluoride salt is sodium monofluorophosphate.

1.0.21. Any of the preceding compositions in which the fluoride salt is sodium fluoride.

1.0.22. Any of the preceding compositions in which the fluoride salt is present in an amount of from about 0.01% by weight to about 2% by weight of the total weight of the composition.

1.0.23. Any of the previous compositions in which the fluoride salt contains a fluoride ion in an amount of from about 0.1 to about 0.2% by weight of the total weight of the composition.

1.0.24. Any of the preceding compositions in which the soluble fluoride salt contains a fluoride ion in an amount of from about 50 to about 25,000 ppm.

1.0.25. Any of the previous compositions, which is a mouthwash containing from about 100 to about 250 ppm of assimilable fluoride ions.

1.0.26. Any of the preceding compositions, which is a toothpaste, having from about 750 to about 2000 ppm of assimilable fluoride ions.

1.0.27. Any of the preceding compositions that contains from about 750 to about 2000 ppm of fluoride ions.

1.0.28. Any of the preceding compositions that contains from about 1000 to about 1500 ppm of fluoride ions.

1.0.29. Any of the previous compositions that contains about 1,450 ppm of fluoride ions.

1.0.30. Any of the preceding compositions in which the pH is from about 6 to about 9, for example from about 6.5 to about 7.4, or from about 7.5 to about 9.

1.0.31. Any of the previous compositions in which the pH is from about 6.5 to about 7.4.

1.0.32. Any of the previous compositions in which the pH is from about 6.8 to about 7.2.

1.0.33. Any of the previous compositions in which the pH is close to neutral.

1.0.34. Any of the preceding compositions further comprising an abrasive or particles.

1.0.35. The immediately preceding composition, in which the abrasive or particles are selected from sodium bicarbonate, calcium phosphate (e.g. dicalcium dihydrate phosphate), calcium sulfate, calcium carbonate (e.g. precipitated calcium carbonate), silicon (e.g. hydrated silicon), iron oxide, oxide aluminum, perlite, plastic particles, such as polyethylene, and combinations thereof.

1.0.36. The immediately preceding composition in which the abrasive or particles are selected from calcium phosphate (e.g., dicalcium dihydrate phosphate), calcium sulfate, precipitated calcium carbonate, silicon (e.g. hydrated silicon), and combinations thereof.

1.0.37. Any of the above compositions, optionally containing an abrasive in an amount of about 15% to about 70% by weight of the total weight of the composition.

1.0.38. Any of the above compositions, optionally containing a fraction of at least about 5% of abrasive microparticles, the average diameter d50 of which is less than about 5 microns.

1.0.39. Any of the above compositions having an RDA of less than about 150, for example from about 40 to about 140.

1.0.40. Any of the above compositions, optionally containing funds against tartar.

1.0.41. Any of the above compositions, optionally containing anti-tartar agents that are polyphosphate, for example pyrophosphate, tripolyphosphate or hexametaphosphate, for example, in the form of a sodium salt.

1.0.42. Any of the above compositions, optionally containing at least one surfactant.

1.0.43. Any of the above compositions, optionally containing at least one surfactant selected from sodium lauryl sulfate, cocamidopropyl betaine, and combinations thereof.

1.0.44. Any of the above compositions, optionally containing anionic surfactant.

1.0.45. Any of the above compositions, optionally containing sodium lauryl sulfate.

1.0.46. Any of the preceding compositions further comprising at least one moisturizer.

1.0.47. Any of the above compositions, optionally containing at least one moisturizer selected from glycerin, sorbitol, xylitol, and combinations thereof.

1.0.48. Any of the above compositions further comprising xylitol.

1.0.49. Any of the above compositions, optionally containing at least one polymer.

1.0.50. Any of the above compositions, optionally containing at least one polymer selected from polyethylene glycols, copolymers of polyvinyl methyl ethers and maleic acid, polysaccharides (e.g. cellulose derivatives such as carboxymethyl cellulose or polysaccharide resins, e.g. xanthan gum or carrageenan) and combinations thereof.

1.0.51. Any of the above compositions, optionally containing ribbons or fragments of resin.

1.0.52. Any of the above compositions, optionally containing flavoring, fragrance and / or coloring.

1.0.53. Any of the above compositions, optionally containing water.

1.0.54. Any of the above compositions containing an antibacterial agent selected from halogenated diphenylether (e.g. triclosan), herbal extracts and essential oils (e.g. rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvinacrol, citral, catechol, methylsalicylic acid ester, epigallocatechin gallate, epigallocatechin, gallic acid, miswack extract, buckthorn buckthorn extract), biguanide antiseptics (e.g. chlorhexidine, alexidine or octenidine ), quaternary ammonium compounds (for example, cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TLC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidinodin, deltinidinodin, deltinidinodina, octenidinodine, salifluoro (5-n-octanoyl-3'-trifluoromethyl-salicylanilide), metal ions (e.g. zinc salts such as zinc citrate, tin salts, copper salts, iron salts), propolis and oxygenating agents (e.g. hydrogen peroxide, buffered peroxyborate or sodium peroxycarbonate), phthalic ki lots and its salts, monoperphthalic acid and its salts and esters, ascorbyl stearate, oleoyl-sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domifen bromide, delmopinol, octapinol and other piperidine derivatives, mixtures of chloroperic acid, mixtures of n any of the above means.

1.0.55. Any of the above compositions, optionally containing an anti-inflammatory compound, for example, an inhibitor of at least one of the initial pro-inflammatory factors selected from matrix metalloproteinases (MMPs), cyclooxygenases (COX), prostaglandin E ₂ (PGE ₂ ), interleukin-1 (IL-1) , IL-1β-converting enzyme (ICE), transforming growth factor β1 (TGF-β1), inducible nitric oxide synthase (iNOS), hyaluronidase, cathepsins, nuclear factor kappa-B (NF-κB) and IL-1 receptor associated kinase (IRAK), which are selected, for example, from ac pyrin, ketorolac, flurbiprofen, ibuprofen, naproxen, methindole, aspirin, ketoprofen, piroxicam, meclofenamic acid, nordigidroguayaret acid and mixtures thereof.

1.0.56. Any of the above compositions, optionally containing an antioxidant, which is selected, for example, from the group consisting of coenzyme Q10, PQQ, vitamin C, vitamin E, vitamin A, anethole-dithiotion, and mixtures thereof.

1.0.57. Any of the above compositions containing an antibacterial agent with poor solubility, for example with a solubility not higher than that of triclosan.

1.0.58. Any of the above compositions in which the antibacterial agent contains triclosan.

1.0.59. Any of the above compositions containing triclosan and xylitol.

1.0.60. Any of the above compositions containing triclosan, xylitol and precipitated calcium carbonate.

1.0.61. Any of the above compositions, optionally containing triclosan and a source of Zn ^{2+ ion} , for example, zinc citrate.

1.0.62. Any of the above compositions, optionally containing an antibacterial agent in an amount of from about 0.01 to about 5% by weight of the total weight of the composition.

1.0.63. Any of the above compositions, optionally containing triclosan in an amount of from about 0.01 to about 1% weight. based on the total weight of the composition.

1.0.64. Any of the above compositions, optionally containing triclosan in an amount of about 0.3% of the total weight of the composition.

1.0.65. Any of the above compositions further comprising a whitening agent.

1.0.66. Any of the above compositions, optionally containing a whitening agent selected from an active bleach, which is selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, hypochlorites, and combinations thereof.

1.0.67. Any of the above compositions, optionally containing hydrogen peroxide or a source of hydrogen peroxide, e.g. urea peroxide or peroxide salt or complex (e.g., such as peroxyphosphate, peroxycarbonate, perborate, peroxysilicate or persulfate salts; for example, calcium peroxyphosphate, sodium perborate, sodium carbonate peroxide, sodium peroxyphosphate and potassium persulfate), or polymer complexes of hydrogen peroxide, such as polymer complexes of polyvinylpyrrolidone - hydrogen peroxide.

1.0.68. Any of the above compositions, optionally containing an agent that inhibits or prevents the fixation of bacteria, such as solbrol or chitosan.

1.0.69. Any of the above compositions, optionally containing a source of calcium and phosphate selected from (i) calcium-glass complexes, for example calcium-sodium phosphosilicates, and (ii) calcium-protein complexes, for example casein-phosphopeptide-amorphous calcium phosphate.

1.0.70. Any of the above compositions, optionally containing a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.

1.0.71. Any of the above compositions, optionally containing a physiologically acceptable potassium salt, for example, potassium nitrate or potassium chloride, in an amount effective to reduce the sensitivity of dentin.

1.0.72. Any of the above compositions, optionally containing from about 0.1% to about 7.5% of a physiologically acceptable potassium salt, for example potassium nitrate and / or potassium chloride.

1.0.73. Any of the above compositions, which is a toothpaste containing an arginine salt, for example arginine hydrochloride, arginine phosphate or arginine bicarbonate; triclosan; anionic surfactant, for example sodium lauryl sulfate; and soluble fluoride salt, for example sodium monofluorophosphate or sodium fluoride.

1.0.74. Any of the above compositions effective for use in the oral cavity, for example, when brushing (i) to reduce or prevent the formation of dental caries, (ii) to reduce, repair or prevent precarious enamel damage, for example, detected by quantitative light fluorescence (QLF) or electrometric method for determining caries (ECM), (iii) to reduce or prevent demineralization and facilitate remineralization of teeth, (iv) to reduce tooth sensitivity, (v) to reduce sludge prevention of gingivitis, (vi) to promote healing of ulcers and wounds in the oral cavity, (vii) to reduce the number of bacteria producing acid, (viii) to increase the relative content of arginolytic bacteria, (ix) to prevent the formation of microbial biofilms in the oral cavity, (x) increasing and / or maintaining, after sugar loading, the pH of plaque at least at a pH of 5.5, (xi) reducing plaque formation, (xii) treating, alleviating or reducing dry mouth syndrome; (xiii) for cleansing the teeth and oral cavity; (xiv) reducing erosion, (xv) whitening teeth and / or (xvi) increasing tooth resistance against cariogenic bacteria.

1.0.75. A composition created or obtained by combining components, according to the formulations for any of the above compositions.

1.0.76. Any of the above compositions in a form selected from a mouthwash, toothpaste, tooth gel, tooth powder, non-abrasive gel, mousse, foam, mouth spray, lozenges, oral tablets, dental implant and pet care product.

1.0.77. Any of the above compositions comprising a toothpaste.

1.0.78. Any of the above compositions, which is a toothpaste, which optionally additionally contains one or more of one or more of the following components: water, abrasive, surfactant, foaming agents, vitamins, polymers, enzymes, moisturizers, thickeners, antibacterial substances, preservatives, flavorings , colorants and / or combinations thereof.

1.0.79. Any of the above compositions 1.0-1.0.76, which is a mouthwash.

1.0.80. Any of the above compositions, optionally containing a breath freshener, fragrance or flavor.

In another embodiment, the invention includes a composition according to the invention (composition 1.1), for example, corresponding to any of the above compositions 1.0-1.0.80, which contains

(i) an effective amount of a salt of a basic amino acid;

(ii) an effective amount of soluble fluoride salt;

(iii) an anionic surfactant, for example sodium lauryl sulfate;

(iv) an anionic polymer, for example a copolymer of methyl vinyl ether and maleic anhydride; and

(v) an antibacterial agent, for example triclosan.

In another embodiment, the invention includes a composition according to the invention (composition 1.2), for example, corresponding to any of the above compositions 1.0-1.0.80, which contains

i. an effective amount of a salt of a basic amino acid;

ii. an antibacterial agent, for example triclosan;

iii. an effective amount of soluble fluoride salt and

iv. abrasive microparticles with which the composition has an RDA of less than about 160, for example from about 40 to about 140, for example, contains at least about 5%, for example at least about 20% of abrasive particles having a d50 of less than about 5 microns for example, silicon particles having a d50 of from about 3 to about 4 microns.

In another embodiment, the scope of the invention includes a method (method 2) for improving oral health, comprising applying to the oral cavity of a subject in need thereof an effective amount of an oral composition according to any of the embodiments for compositions 1.0, 1.1, or 1.2, for example, a method for

(i) reduce or prevent the formation of dental caries;

(ii) reducing, repairing, or preventing early damage to the enamel, such as detected by quantitative light fluorescence (QLF) or electrometric caries detection (ECM);

(iii) reduce or prevent demineralization and facilitate remineralization of teeth;

(iv) reducing tooth sensitivity;

(v) reducing or preventing gingivitis;

(vi) promoting the healing of ulcers and wounds in the oral cavity;

(vii) reducing the number of bacteria that produce acid;

(viii) increasing the relative content of arginolytic bacteria;

(ix) preventing the formation of a microbial biofilm in the oral cavity;

(x) increasing and / or maintaining after sugar loading the pH of the plaque at least at a pH of 5.5;

(xi) reduce plaque formation;

(xii) treating, alleviating or reducing dry mouth syndrome;

(xiii) strengthening overall health, which includes cardiovascular health, for example, by reducing the likelihood of a general infection through the tissues of the oral cavity;

(xiv) teeth whitening;

(xv) reducing erosion;

(xvi) increase tooth resistance against cariogenic bacteria and / or

(xvii) for cleansing the teeth and oral cavity.

The present invention further comprises the use of arginine in the manufacture of a composition according to the invention, for example, for use in any of the indications formulated for method 2.

The present invention further relates to a composition for caring for the oral cavity, containing a basic amino acid in free or salt form and an antibacterial agent for use in the antibacterial treatment of an oral cavity in a subject.

The present invention further relates to a composition for caring for the oral cavity containing an antibacterial agent and a basic amino acid in free or salt form to increase the delivery of an antibacterial agent to a surface in a subject's oral cavity.

The present invention further relates to the use of a basic amino acid in free or salt form in an oral care composition that contains an antibacterial agent, for enhancing the delivery of an antibacterial agent to a surface in the oral cavity of a subject, and to the use of a basic amino acid in free or in form salts for the manufacture of a medicament which contains an antibacterial agent for use in order to increase the delivery of an antibacterial agent to the surface in the mouth howling cavity of the subject.

The present invention further relates to a method for increasing the delivery of an antibacterial agent from an oral composition to an oral surface of a subject, to a method that comprises treating an oral cavity with an oral composition containing an antibacterial agent and free form basic amino acid or in the form of salt.

A qualified specialist in the field of oral care may note that the unexpected effectiveness of the technique and the advantage of increased delivery of antibacterial agents to the teeth may be due to the formulation and use of the composition for caring for the oral cavity, for example toothpaste, according to one or more aspects of the present invention that are aimed to provide combinations of active ingredients or ingredients and, preferably, their respective amounts in the composition.

The antibacterial agent can be selected from halogenated diphenyl ether (e.g. triclosan), herbal extracts and essential oils (e.g. rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, hinoktiol, catechol, ether methylis epigallocatechin gallate, epigallocatechin, gallic acid, miswaka extract, buckthorn buckthorn extract), biguanide antiseptics (e.g. chlorhexidine, alexidine or octenidine), quaternary ammonium compounds (e.g. p, cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TLC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, octenidine, sanguinarine, povdoline-5, deldinodine -octanoyl-3'-trifluoromethyl-salicylanilide), metal ions (e.g. zinc salts such as zinc citrate, tin salts, copper salts, iron salts), propolis and oxygenating agents (e.g. hydrogen peroxide, buffered peroxyborate or sodium peroxycarbonate) , phthalic acid and its salts, monoperphthalic acid and e salts and esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol, octapinol, and other piperidine derivatives, nitsina preparations chlorous acid salts and mixtures of any of the above means.

The composition may further comprise an anti-inflammatory compound, for example, an inhibitor of at least one of the initial pro-inflammatory factors selected from matrix metalloproteinases (MMPs), cyclooxygenases (COX), PGE ₂ , interleukin-1 (IL-1), IL-1β-converting enzyme ( ICE), transforming growth factor β1 (TGF-β1), inducible nitric oxide synthase (iNOS), hyaluronidase, cathepsins, nuclear factor kappa-B (NF-κB) and IL-1 receptor-associated kinase (IRAK), which are selected e.g. from aspirin, ketorolac, flurbiprofen, ibu rofena, naproxen, indomethacin, aspirin, ketoprofen, piroxicam, meclofenamic acid nordigidroguayyaretovoy acid and mixtures thereof. The compositions may also additionally or alternatively contain an antioxidant that is selected, for example, from the group consisting of coenzyme Q10, PQQ, vitamin C, vitamin E, vitamin A, anethole-dithiotion, and mixtures thereof.

The content of active components will vary based on the characteristics of the delivery system, in particular their activity. For example, the content of the basic amino acid can vary from about 0.1 to about 20% by weight (i.e., the weight of the free base), for example from about 0.1 to about 3% by weight, in a mouthwash, from about 1 to about 10% weight in consumer toothpaste or from about 7 to about 20% of the weight in the product for professional or prescribed treatment. The content of fluoride present may be, for example, from about 25 to about 25,000 ppm, for example from about 25 to about 250 ppm in a mouthwash, from about 750 to about 2000 ppm in a consumer toothpaste or from about 2000 to about 25,000 ppm in the product for professional or prescribed treatment. The content of antibacterial agents will vary in a similar way, while the level of their content used for toothpaste will be, for example, from about 5 to about 15 times higher than in a mouthwash. For example, in a mouthwash, the content of triclosan can be, for example, about 0.03% by weight of triclosan, while the triclosan in toothpaste can be contained in an amount of about 0.3% by weight of triclosan.

Essential Amino Acids

The basic amino acids that can be used in the compositions and methods of the present invention include not only basic amino acids of natural origin, such as arginine, lysine and histidine, but also any basic amino acids having a carboxyl group and an amino group in the molecule that are soluble in water and have the pH of the aqueous solution is about 7 or more.

Thus, basic amino acids include, but are not limited to, arginine, lysine, citrulline, ornithine, creatine, histidine, diaminobutanoic acid, diaminopropionic acid, their salts or combinations thereof. In a specific embodiment, the basic amino acids are selected from arginine, citrulline and ornithine.

In some embodiments, the implementation of the main amino acid is arginine, for example L-arginine or its salt.

In some embodiments, the implementation of the basic amino acid contains at least one intermediate product produced by the arginine deiminase system. Intermediates produced by the arginine deiminase system may be useful in the composition for caring for the oral cavity, to neutralize plaque in order to control and / or prevent caries. Arginine is the main amino acid of natural origin that can be found in the oral cavity. Some bacterial plaque strains, such as S. sanguis, S. gordonii, S. parasangiuis, S. rattus, S. milleri, S. anginosus, S. faecalis, A. naeslundii, A. odonolyticus, L. cellobiosus, L. brevis, L.fermentum, P. gingivalis and T. denticola, can break down arginine in the mouth for their survival. These microorganisms can die in an acidic environment, which is located in areas close to the surface of the teeth, where acidogenic and aciduric cariogenic strains can utilize sugar to produce organic acids. Thus, these arginolytic strains can cleave arginine to ammonia to create an alkaline reaction for its survival and, in addition, to delimit the spot zone and the formation of an aggressive environment of the cariogenic system.

These arginolytic organisms can break down arginine using an internal cellular enzymatic metabolic system called the arginine deiminase system, in which intermediate metabolic products are formed. In this process, L-arginine can be cleaved by arginine deiminase to L-citrulline and ammonia. L-citrulline can then be cleaved by ornithine transcarbamylase in the presence of inorganic phosphate to L-ornithine and carbamyl phosphate. Carbamate kinase, in turn, can cleave carbamyl phosphate to form another ammonia and carbon dioxide molecule, and ATP (adenosine 5'-triphosphate) is also formed in this scheme. Arginolytic bacteria can use ATP as a source of energy for growth. Thus, if the arginine deiminase system is involved, two ammonia molecules can form.

It has been found that in some embodiments, ammonia can help neutralize the pH level of plaque in the oral cavity to control and / or prevent dental caries.

According to some embodiments of the present invention, the oral composition may include intermediates produced by the arginine deiminase system. Such intermediates may include citrulline, ornithine and carbamyl phosphate. In some embodiments, the implementation of another composition for caring for the oral cavity contains citrulline. In some embodiments, the oral composition comprises ornithine. In some embodiments, an oral composition comprises carbamyl phosphate. In other embodiments, the oral composition comprises any combination of citrulline, ornithine, carbamyl phosphate and / or other intermediates produced by the arginine deiminase system.

An oral care composition may include the above described intermediates in an effective amount. In some embodiments, the content of intermediates in the oral composition is from about 1 mmol / L to about 10 mmol / L. In other embodiments, the implementation of the composition for caring for the oral cavity contains from about 3 mmol / l to about 7 mmol / l of intermediate products. In other embodiments, an oral composition contains about 5 mmol / L of intermediate products.

The compositions of the invention are intended for topical use in the mouth and, accordingly, the salts used in the present invention must be safe for the indicated use, in terms of quantity and concentration. Suitable salts include salts known in the art as pharmaceutically acceptable salts, which, in the amount and concentration employed, are generally considered physiologically acceptable. Physiologically acceptable salts include salts formed from pharmaceutically acceptable inorganic or organic acids or bases, for example acid addition salts derived from acids forming a physiologically acceptable anion, such as a hydrochloride or bromide salt, and basic addition salts derived from bases that form physiologically an acceptable cation, for example, salts derived from alkali metals such as potassium and sodium, or alkaline earth metals, such as calcium and magnesium. Physiologically acceptable salts can be prepared using standard procedures known in the art, for example, by reacting a suitable basic compound, such as an amine, with a suitable acid to give a physiologically acceptable anion.

In various embodiments, the basic amino acid is present in an amount of from about 0.5% to about 20% by weight of the total weight of the composition, from about 1% to about 10% of the total weight of the composition, for example, about 1.5% by weight, about 3.75% by weight, about 5% by weight, or about 7.5% by weight of the total weight of the composition.

RDA: The term RDA is an abbreviation for abrasive wear of dentin by the radioactive method, i.e. a relative measure of abrasion. Typically, extracted teeth of a person or cow are irradiated with a neutron flux, fixed in methyl methacrylate (bone glue), stripped of enamel, inserted into a brush machine, with brushes according to American Dental Association (ADA) standards (toothbrush standards: pressure 150 g, 1500 movements, water solution - toothpaste 4 × 1). Then, the radioactivity of the rinse is measured and recorded. To control the experiment, the test was repeated with a toothpaste according to the ADA standard made of calcium pyrophosphate, the measurements obtained in this case had a value of 100 for calibrating the relative scale.

Fluoride ion source

Oral care compositions may further include one or more sources of fluoride ion, for example, soluble fluoride salts. A wide variety of materials that form fluoride ions can be used as sources of soluble fluoride in the compositions of the present invention. Examples of suitable fluoride ion forming materials are given in US Pat. No. 3,535,421 to Briner et al .; US Pat. No. 4,885,155 to Parran, Jr et al. and in US patent No. 3678154 Widder et al., incorporated by reference into the present invention.

Examples of sources of fluoride ion include, but are not limited to, tin fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In some embodiments, the fluoride ion source comprises tin fluoride, sodium fluoride, sodium monofluorophosphate, and mixtures thereof.

In some embodiments, the oral composition for caring for the present invention may also contain a source of fluoride ions or a fluorine-containing component in an amount sufficient to deliver from about 25 ppm to about 25,000 ppm of fluoride ions, generally at least about 500 ppm, for example, from about 500 to about 2000 ppm, for example, from about 1000 to about 1600 ppm, for example, about 1450 ppm. The appropriate level of fluoride content will depend on the particular application. For mouthwashes, for example, a content of from about 100 to about 250 ppm of fluoride will be common. In toothpaste for general consumer use, a content of about 1000 to about 1500 ppm with a slightly lower content in children's toothpaste will be common. In a toothpaste or coating for professional use, fluorides can be contained in an amount of about as much as 5,000, or even about 25,000 ppm.

In one embodiment, sources of fluoride ion can be added to the compositions of the invention in an amount of from about 0.01% to about 10% by weight, or in another embodiment, from about 0.03% to about 5% by weight and from about 0.1 % weight to about 1% weight by weight of the composition in yet another embodiment. Obviously, in order to achieve an appropriate content of fluoride ions, the weight of fluoride salts will vary depending on the weight of the counterion in the salt.

Abrasives

The compositions of the invention may contain a calcium phosphate abrasive, for example tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ), hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ (OH) ₂ ), or dicalcium phosphate dihydrate (CaHPO ₄ • 2H ₂ O, also sometimes referred to in the present invention as DiCaI), or calcium pyrophosphate. Alternatively, calcium carbonate and, in particular, calcium precipitated carbonate can be used as an abrasive.

The compositions may include one or more additional abrasives, for example silicon abrasives, such as precipitated silicon compounds, the average particle size of which is up to about 20 microns, for example Zeodent 115® sold by J. M Huber Corp. Other useful abrasives also include sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite, or other silicon-containing materials, or combinations thereof.

Silicon polishing abrasives useful in the present invention, as well as other abrasives, typically have an average particle size in the range of about 0.1 to about 30 microns, about 5 to about 15 microns. Silicon abrasives can be obtained from precipitated silicon or silica gels, such as silicon xerogels described in US patent No. 3538230 Pader et al. and in US patent No. 3862307, Digiulio, and both of these patents are incorporated with reference to the invention. Specific silicon xerogels are sold under the trademark Syloid by W.R. Grace & Co., Davison Chemical Division. Precipitated silicon materials include materials sold by J. M Huber Corp. under the trademark Zeodent®, and include silicon-containing compounds under the designation Zeodent 115 and 119. These silicon abrasives are described in US patent No. 4340583, Wason, incorporated into the invention by reference.

In some embodiments, abrasive materials useful for the compositions for an oral care implement according to the invention include silica gels and precipitated amorphous silica with an oil absorption ratio of less than about 100 cm ^3/100 g silica and in the range from about 45 cm ^3/100 g to about 70 cm ^3/100 g silica. The oil absorption coefficient is measured by grinding the pigment with oil according to ASTM Method D281. In some embodiments, the colloidal silicon particles have an average size of from about 3 microns to about 12 microns and from about 5 to about 10 microns.

In specific embodiments, the abrasive materials comprise a large fraction of very fine particles with an average diameter of d50 of less than about 5 microns, for example in finely divided silicon (MDC), the d50 is from about 3 to about 4 microns, for example in Sorbosil AC43® (Ineos). Such microparticles are especially useful in formulations designed to reduce hypersensitivity. The finely divided component may be present in combination with a second abrasive with larger particles. For example, in some embodiments, the formulation contains from about 3 to about 8% microparticles, for example, MDK, and from about 25 to about 45% of a conventional abrasive.

Silicon abrasives with low oil absorption, especially useful for carrying out the invention, are sold under the trademark Sylodent XWA® by Davison Chemical Division, WR Grace & Co., Baltimore, Md. 21203. silica hydrogel Sylodent 650 XWA® *, consisting of colloidal silica particles with a water content of about 29 weight%, with an average particle diameter of from about 7 to about 10 microns and an oil absorption of less than about 70 cm ^3/100 g silica, is is an example of a silicon abrasive with a low oil absorption coefficient, is useful for the implementation of the present invention. The concentration of abrasive in the oral composition of the present invention is from about 10 to about 60% by weight, in another embodiment from about 20 to about 45% by weight, and in yet another embodiment, from about 30 to about 50% by weight.

In some embodiments, the implementation of the basic amino acid is included in the composition of the toothpaste having a basic formulation containing calcium carbonate, and, in particular, contains precipitated calcium carbonate as an abrasive. L-arginine and arginine salts themselves, such as arginine bicarbonate, have a distinctly bitter taste, and a fishy taste can also be transmitted in the aqueous solution. Therefore, it was assumed that the taste and mouthfeel of the toothpaste formulations were degraded when L-arginine or arginine salts were included in effective concentrations in oral care products, for example in toothpaste formulations, to give them anti-caries effectiveness and to reduce sensitivity, usually in amount from 2 to 10% of the weight, calculated on the total weight of the toothpaste formulation, compared with a similar formulation without the addition of arginine salts or L-arginine.

However, it was unexpectedly discovered according to this aspect of the present invention that the addition of L-arginine or arginine salts to a basic calcium carbonate toothpaste formulation can significantly improve the taste and mouthfeel of said toothpaste formulation and increase overall consumer acceptance of the product. .

Means for increasing the amount of foam

Compositions for caring for the oral cavity according to the invention may also include means for increasing the amount of foam that is formed when brushing the oral cavity.

Illustrative examples of agents that increase the amount of foam include, without limitation, polyoxyethylene and some polymers, including without limitation alginate polymers.

Polyoxyethylene can increase the amount of foam and the thickness of the foam formed by the oral carrier component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol (PEG) or polyethylene oxide. The molecular weight of suitable polyoxyethylenes present invention is from about 200,000 to about 7,000,000 In one embodiment the molecular weight will be about 600,000 to about 2,000,000 and in another embodiment from about 800,000 to about 1,000,000 Trade mark is a high polyoxyethylene Polyox ^®, produced by Union Carbide.

Polyoxyethylene may be present in an amount of from about 1% to about 90%, in one embodiment, from about 5% to about 50%, and in another embodiment, from about 10% to about 20% by weight of an oral care carrier component of the compositions for care for the oral cavity of the present invention. The content of the foaming agent in the oral composition (i.e., a monolithic dose) is from about 0.01 to about 0.9% by weight, from about 0.05 to about 0.5% by weight, and in another embodiment, from about 0 , 1 to about 0.2% of the weight.

Surfactants

Another agent optionally included in the oral composition of the present invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants are surfactants with acceptable stability over a wide pH range, for example anionic, cationic, nonionic or zwitterionic surfactants.

Suitable surfactants are more fully described, for example, in US Pat. No. 3,959,458 to Agricola et al .; in US patent No. 3937807 Haefele and in US patent No. 4051234 Gieske et al., which are included in the invention by reference.

In some embodiments, the anionic surfactants useful in the present invention include water-soluble salts of alkyl sulfates having an alkyl radical of about 10 to about 18 carbon atoms, and water-soluble salts of sulfonated fatty acid monoglycerides having from about 10 to about 18 carbon atoms. Sodium lauryl sulfate, sodium lauryl sarcosinate and coconut sodium monoglyceride sulfonates are examples of this type of anionic surfactants. Mixtures of anionic surfactants can also be used.

In another embodiment, cationic surfactants useful for the present invention can be broadly defined as derivatives of quaternary ammonium aliphatic compounds having one long alkyl chain containing from about 8 to about 18 carbon atoms, for example, lauryl trimethylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, diisobutylmethylbenylmethylammonium bromide coconut alkyltrimethylammonium nitrite, cetylpyridinium fluoride and mixtures thereof.

Examples of cationic surfactants are quaternary ammonium fluorides described in US patent No. 3535421 Briner et al., Incorporated by reference in the present invention. Some cationic surfactants in the compositions may also have a bactericidal effect.

Examples of nonionic surfactants that can be used in the compositions of the invention can be broadly referred to as compounds obtained by condensation of alkylene oxide groups (with hydrophilic characteristics) with an organic hydrophobic compound, which may be of an aliphatic or alkyl aromatic nature. Examples of suitable nonionic surfactants include, but are not limited to, pluronics, polyethylene oxide condensates of alkyl phenols, products obtained by condensation of ethylene oxide with a reaction product of propylene oxide and ethylene diamine, ethylene oxide condensates of aliphatic alcohols, long chain tertiary amine oxides, long chain tertiary phosphine oxides and dialkyl sulfides such funds.

In some embodiments, the zwitterionic synthetic surfactants useful in the present invention can be broadly described as derivatives of aliphatic quaternary ammonium, phosphonium and sulfonium compounds in which the aliphatic radicals can be straight or branched chain, and in which one of the aliphatic substituents contains from about 8 to about 18 carbon atoms, and each contains an anionic water-soluble group, for example, carboxy, sulfonate, sulfate, phosphate or phosphonate. Illustrative examples of surfactants suitable for inclusion in the composition include, without limitation, sodium alkyl sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine, polysorbate 20, and combinations thereof.

In a specific embodiment, the composition of the invention comprises an anionic surfactant, for example sodium lauryl sulfate.

A surfactant or a mixture of compatible surfactants may be present in the compositions of the present invention in an amount of from about 0.1% to about 5.0%, in another embodiment from about 0.3% to about 3.0%, and in another embodiment from about 0 5% to about 2.0% of the total weight of the composition.

Flavors

Oral care compositions of the invention may also include a flavoring agent. Flavors that are used to implement the present invention include, without limitation, essential oils, as well as various aromatic aldehydes, esters, alcohols, and the like. Examples of essential oils include crispy peppermint oil, peppermint oil, wintergreen oil, sassafras oil, clove oil, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange oils. Chemicals such as menthol, carvone and anethole are also useful. In some embodiments, spearmint and peppermint oils are used.

Flavoring agents are included in the composition at a concentration of from about 0.1 to about 5% by weight and from about 0.5 to about 1.5% by weight. The dose of flavoring in an individual dose of an oral composition (i.e., a monolithic dose) is from about 0.001 to about 0.05% by weight, and in another embodiment, from about 0.005 to about 0.015% by weight.

Chelating agents

Compositions for caring for the oral cavity according to the invention may also optionally include one or more chelating agents capable of forming complexes with calcium located in the bacterial cell wall. The binding of this calcium weakens the bacterial cell wall and enhances bacterial lysis.

Another group of agents suitable for use in the present invention as chelating agents is soluble pyrophosphates. The pyrophosphate salts used in the compositions of the present invention can be any of the alkali metal pyrophosphate salts. In some embodiments, the salts include alkali metal tetrapyrphosphate, bis alkali metal bis pyrophosphate, tri-alkali mono-acid pyrophosphate, and mixtures thereof, the alkali metals being sodium or potassium. Salts are useful in both their hydrated and unhydrated forms. An effective amount of the pyrophosphate salt useful in the composition of the present invention is generally sufficient to provide at least about 1.0% weight of the pyrophosphate ion, from about 1.5% weight to about 6% weight, from about 3.5% weight to about 6% of the weight of these ions.

Polymers

Oral care compositions of the invention also optionally include one or more polymers such as polyethylene glycols, copolymers of polyvinyl methyl ether and maleic acid, polysaccharides (e.g., cellulose derivatives, such as carboxymethyl cellulose, or polysaccharide resins, e.g. xanthan gum or carrageenan). Acidic polymers, for example polyacrylate gels, can be present in the form of their free acids or partially, or fully neutralized, water-soluble alkali metal (e.g. potassium and sodium) or ammonium salt.

In particular, if non-cationic antibacterial agents or antibacterial agents, for example triclosan, are included in any of the components of the toothpaste, it is also preferable to include from about 0.05 to about 5% of the agent, which increases the delivery and retention of the funds and their retention by the surfaces of the oral cavity. Such agents useful in the present invention are disclosed in US Pat. Nos. 5,188,821 and 5,192,531 and include synthetic anionic polymer polycarboxylates, such as copolymers of 1: 4 to 4: 1 maleic anhydride or an acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether / maleic anhydride having a molecular weight (MM) from about 30,000 to about 1,000,000, most preferably from about 30,000 to about 800,000. These copolymers are available, for example, under the brand name Gantrez, for example 139 (MM 500,000), 119 (MM 250,000) and will prefer flax S-97 Pharmaceutical Grade (MW 700,000), from the company ISP Technologies Inc .. Bound Brook, N.J. 08805. Amplifying agents, if any, are present in an amount of from about 0.05 to about 3% by weight.

Other active polymers include a 1: 1 copolymer of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, while ethylene, for example, is available under the brands Monsanto EMA No. 1103 with MM 10000 and EMA grade 61, and 1: 1 copolymer of acrylic acid with methyl or hydroxyethyl methacrylate, methyl or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

Suitable in general are polymerized olefinic or ethylenically unsaturated carboxylic acids containing an activated carbon-carbon olefinic double bond and at least one carboxylic acid group, i.e. an acid containing an olefinic double bond, which polymerizes easily due to the presence of monomer in the molecule as in the alpha-beta position relative to the carboxyl group or as part of the terminal methylene group. Examples of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxy-propionic, sorbic, alpha-chlorosorbic, cinnamon, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutaconyl, alcon, 2-benzyl acrylic, 2-cyclohexyl acrylic, angelic, umbellic, fumaric, maleic acids and anhydrides. Other various olefin monomers copolymerizable with said carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate and the like. The copolymers contain suitable groups of carbon salts for solubility in water.

An additional class of polymeric agents includes a composition containing homopolymers of substituted acrylamides and / or homopolymers of unsaturated sulfonic acids and their salts, in particular with polymers based on unsaturated sulfonic acids selected from acrylamidoalkanoic sulfonic acids, for example 2-acrylamido-2-methylpropane sulfonic acid with a molecular weight of from about 1,000 to about 2,000,000, which is described in US patent No. 484284727 of June 1989 by Zahid, incorporated herein by reference.

Another useful class of polymeric agents comprises polyamino acids, in particular containing proportions of anionic surfactant amino acids such as aspartic acid, glutamic acid and phosphoserine, according to the disclosure of US Pat. No. 4,866,161 to Sikes et al., Which is incorporated herein by reference.

Sometimes, for the manufacture of oral care compositions, it is necessary to add some thickening agent to achieve the desired consistency or to stabilize or enhance the effect of the formulation. In some embodiments, the thickening agents are carboxyvinyl polymers, carrageenan, hydroxyethyl cellulose and water soluble salts of cellulose ethers such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Resins of natural origin such as karaya, gum arabic and tragacanth resin may also be included. Colloidal magnesium aluminum silicate or finely divided silicon can be used as a component of the thickener composition to further improve the texture of the composition. In some embodiments, thickeners are used in an amount of from about 0.5% to about 5.0% of the total weight of the composition.

Enzymes

Oral care compositions of the invention may also optionally include one or more enzymes. Useful enzymes include any of the available enzymes: proteases, glucanohydralases, endoglycosidases, amylases, mutanases, lipases and mucinases, or compatible mixtures of these enzymes. In some embodiments, the enzyme is a protease, dextranase, endoglycosidase, and mutanase. In another embodiment, the enzyme is papain, endoglycosidase, or a mixture of dextranase and mutanase. Additional enzymes suitable for use in the present invention are disclosed in US Pat. No. 5,000,939 to Dring et al. In US Pat. No. 4,992,420; in US patent No. 4355022; in US patent No. 4154815; in US patent No. 4058595; in US patent No. 3991177 and in US patent No. 3696191, all of which are included in the present invention with reference. The amount of enzyme in the mixture of several compatible enzymes in the present invention is from about 0.002% to about 2.0% in one embodiment, or from about 0.05% to about 1.5% in another embodiment, or in yet another embodiment, from about 0.1% to about 0.5%.

Water

Water may also be present in the oral compositions of the invention. The water used to make the sold oral care compositions should be deionized and free of organic impurities. Water usually constitutes the rest of the compositions and is contained in an amount of from about 10% to about 90%, from about 20% to about 60%, or from about 10% to about 30% of the weight of the oral compositions. The indicated amount of water includes the free water that is added, plus the amount that is administered with other means, for example sorbitol or any of the components of the present invention.

Moisturizers

In some embodiments, it is also desirable to include a moisturizer in the oral composition to prevent the composition from hardening when exposed to air. Some moisturizing agents may also give the toothpaste compositions the desired sweet taste or aroma. In a toothpaste composition, a pure moisturizing moisturizer is typically included in an amount of from about 15% to about 70% in one embodiment, or from about 30% to about 65% in another embodiment of the weight of the composition.

Suitable humectants include edible polyhydric alcohols, such as glycerin, sorbitol, xylitol, propylene glycol, as well as other polyols and mixtures of these humectants. Mixtures of glycerol and sorbitol can be used in some embodiments as a moisturizing component of the toothpaste compositions of the present invention.

In addition to the above described components, embodiments of the present invention may contain many additional components of toothpaste, some of which are described below. Additional components include, but are not limited to, for example, adhesives, blowing agents, flavoring agents, sweeteners, additional anti-plaque agents, abrasives and colorants. These and other additional components are further described in US patent No. 5004597, Majeti; US Pat. No. 3,959,458 to Agricola et al. and US Pat. No. 3,937,807 to Haefele, all of which are incorporated herein by reference.

Manufacturing methods

The compositions of the present invention can be prepared using methods generally accepted in the oral product field.

In one exemplary embodiment, the oral composition is prepared by neutralizing or partially neutralizing the gel phase arginine with an acid, for example phosphoric acid, hydrochloric acid or carbon dioxide, and mixing to form premix I.

Active agents such as, for example, vitamins, cetylpyridinium chloride (CPC), fluoride, abrasives and any other desired active ingredients are added to premix I and mixed to form premix II.

If the final product is toothpaste, a toothpaste base, such as dicalcium phosphate or silicon, is added to premix II and mixed. The final liquid mass is formed into an oral care product.

Composition application

The present invention in relation to the method covers the use in the oral cavity of a safe and effective amount of the described compositions.

Compositions and methods according to the invention are useful for a method of protecting teeth, which leads to their assistance in restoration and remineralization, in particular to reduce or stop the formation of dental caries, reduce or prevent demineralization and accelerate remineralization of teeth, reduce tooth sensitivity and reduce, restore or prevent early enamel damage, for example, detected by quantitative light fluorescence (QLF) or by electrometric determination caries (ECM).

Quantitative light fluorescence is the visible light fluorescence that can detect early damage and continuously monitor their development or regression. Normal teeth fluoresce in the visible light spectrum: with the demineralization of teeth, this phenomenon is not observed or it is detected to a lesser extent. The demineralization zone can be quantified and control over its development is possible. To cause autofluorescence of the teeth, a blue laser beam is used. In demineralized zones, lower fluorescence is noted, and they appear darker compared to the surface of a healthy tooth. Software is used to quantify fluorescence from white spots or the area / volume associated with damage. In general, subjects with identified lesions in the form of white spots become participants in the study. Measurements are carried out in vivo with real teeth. Zones / volume of damage is measured at the start of a clinical trial. The reduction (improvement) of the area / volume of damage is measured in total after 6 months of product use. Data is often given as a percentage of improvement over baseline.

The electrometric method for determining caries (ECM) is a technique for measuring the mineral composition of a tooth based on electrical resistance. The electrical conductivity measurement is based on the fact that microtubules filled with liquid undergo demineralization and enamel damage, and they pass an electric current. With the loss of minerals in the tooth, resistance to electric current decreases due to increased porosity. Therefore, an increase in the conductivity of the patient’s teeth may indicate demineralization. Usually, studies are carried out at the root surface with an existing lesion. Measurements are carried out in vivo on real teeth. Determine changes in electrical resistance before treatment and after 6 months of treatment. In addition, a classic caries count is performed on the surface of the roots using a tactile study. Hardness is classified on a three-point scale: hard, leathery or soft. When measuring ECM in a study of this type, the results are usually given as indicators of electrical resistance (better, higher) and data on the increase in hardness in the affected area based on the tactile test scale.

Thus, the compositions of the invention are useful for reducing early enamel lesions (as determined by QLF or ECM) compared with a composition with an insufficiently effective amount of fluorine and / or arginine.

The compositions of the invention are additionally useful for reducing harmful bacteria in the oral cavity, for example, for reducing or stopping the development of gingivitis, reducing the acid content produced by bacteria, increasing the relative content of arginolytic bacteria, stopping the formation of a microbial biofilm in the oral cavity, increasing and / or maintaining after sugar pH plaque loading of at least about 5.5, to reduce plaque buildup and / or brushing your teeth and mouth.

Finally, by increasing the pH level in the mouth and preventing the growth of pathogenic bacteria, the compositions of the invention are useful for accelerating the healing of ulcers and wounds in the oral cavity.

Improving oral health also provides health benefits for the body as a whole, as oral tissue can be a gateway to systemic infection. A healthy state of the oral cavity is associated with the health of the body, in general, including the health of the cardiovascular system. The compositions and methods of the invention are particularly useful since basic amino acids, in particular arginine, serve as a nitrogen source that provides NO synthesis pathways and thus improves microcirculation in the tissues of the oral cavity. Achieving a less acidic environment in the oral cavity is also beneficial in reducing gastric upset and creates an environment less favorable for Helicobacler, which is associated with a stomach ulcer. Arginine is especially necessary for the high expression of specific immune cell receptors, for example T-cell receptors, that is, arginine can enhance an effective immune response. Thus, the compositions and methods of the present invention are useful for enhancing the health of the body as a whole, including the health of the cardiovascular system.

Compositions and methods according to the invention can be included in compositions for caring for the oral cavity and teeth, for example, toothpastes, transparent pastes, gels, mouthwashes, sprays and chewing gums.

Ranges used throughout the present invention are used to briefly describe each value within a range. Any value in the range can be selected as the limit of the range. Additionally, all references cited in the invention are incorporated by reference in their entirety. In the event of a contradiction between the concepts in the present disclosure and the concepts from the cited reference, control remains with the disclosure. It is understood that in the description of the formulations, a description is possible with respect to their components, which is generally accepted in the art, although these components can react with each other in the actual formulation during its manufacture, storage and use, and such products are considered to be included in the volume of the described recipes.

The following examples further describe and demonstrate examples of embodiments within the scope of the present invention. The examples are given for illustration only and should not be construed as limiting the present invention, since many changes can be made without departing from the essence and scope of the invention. Various modifications in addition to those shown and described in the present invention are obvious to a person skilled in the art and are considered to be included in the scope of the attached claims.

EXAMPLES

Example 1

Digestibility and delivery of antibacterial agents in formulations with arginine

The formulations were prepared using a commercially available toothpaste containing, ia, 0.3% by weight triclosan, 0.243% by weight sodium fluoride, sodium lauryl sulfate and a copolymer of methyl vinyl ether and maleic anhydride (PVM / MA), to which 0.1%, 3 was added % and 5% L-arginine hydrochloride (pH 7.0).

The inclusion of L-arginine in a commercial formulation increases the amount of soluble triclosan digestible from the formulation from about 70% (0% arginine) to about 80% (1% arginine), 85% (3% arginine) and 95% (5% arginine )

The formulations were tested in vitro in an artificial oral model designed to measure the attachment of bacteria to hydroxyapatite (HAP) disks treated with toothpaste for 24 hours, generally as described by Gaffar, A. et al. American Journal of Dentistry, vol. 3. September 1990, with a modification when saliva-coated hydroxyapatite discs were treated with a liquid mass of toothpaste before exposure to bacteria. It was shown that the inclusion of L-arginine in the commercial formulation increases the delivery of triclosan to disks by about 50%, with an increase in capture at a point in time of 30 minutes from about 40 μg of triclosan in the control disk to about 60 μg of triclosan with a formulation of 5% arginine. After 24 hours, control discs retained about 10 μg per disk, compared with the presence of about 20 μg of 5% arginine formulation, which is significantly higher. Similar results were achieved using histidine or lysine instead of arginine.

This increased delivery directly leads to an increase in the antibacterial effect of the formulation with a statistically significant decrease of approximately 15% inhibition of A. viscosus growth when using 5% arginine formulation compared to the control.

Example 2

Preparation of silicon-based arginine formulations

Toothpaste formulations containing 5% silicon-based arginine were prepared as follows.

A premix solution (premix I) was prepared by dissolving sodium fluoride and sodium saccharin in part of the amount of H ₂ O in the formulation. Polymer resins and titanium dioxide were dispersed in a separate container in wetting agents. Premix I was added to the gel phase and heated if necessary.

Another premix solution (premix II) was prepared by first dispersing L-arginine in a portion of the water from the formulation. The PVM / MA mixture (Gantrez) was then added to the dispersion of L-arginine and mixed until homogeneous. The pH of the gel phase could then be adjusted to a neutral pH by adding an appropriate amount of inorganic acid or base. Then premix II was added to the humidifier / polymer resin solution to complete the gel phase.

The gel phase was transferred to a suitable vessel for production. Abrasives were added to the gel phase and mixed under vacuum until homogeneous. Finally, triclosan, flavor and surfactant were added to the mixture and mixed under vacuum until homogeneous.

Formula: Triclosan Plus L-Arginine

Content % weight / weight Sorbitol - not darkening / not crystallizing 20.85 99.0% -101.0% Vegetable Glycerin - USP and EP 20,0 Gantrez s-97 2.0 Dental Silicon-Zeodent 105-High Purity Silicon 10 Dental Silicon (Zeodent 115) Abrasive 8.5 L-arginine 5,0 Dental Silicon Zeodent 165 - Synthetic Amorphous Ppt Silicon 3.0 Powder - Sodium Lauryl Sulfate NF 1,5 Solution of 50% sodium hydroxide (grade for reagent) 1,2 Sodium CPC-12 USP Type 1,1 Flavoring 1,0 Hydrochloric acid 0.9 USP Titanium Dioxide 0.75 Propylene glycol - USP 0.5 Carrageenan (LB 9505) 0.40 Triclosan - USP 0.3 Sodium Saccharin USP 0.3 Sodium Fluoride USP 0.243 Demineralized water Qs

Additional formulations were prepared as follows.

Example 3

The effectiveness of the formulations in the absorption of triclosan and the addition of bacteria

We studied the capture of triclosan by applying the liquid mass of toothpaste to saliva-coated hydroxyapatite discs for a set time at 37 ° C. The discs were rinsed to remove excess toothpaste on the surface. The active agent, which was applied to the disk, was then dissolved and analyzed by high performance liquid chromatography (HPLC). A commercial toothpaste having a formulation similar to formula II of Example 2 above, containing, ia, 0.3% by weight triclosan, 0.243% by weight sodium fluoride, sodium lauryl sulfate and a copolymer of methyl vinyl ether and maleic anhydride, but without arginine, is reliable management. The indicated positive control had a triclosan uptake of 32.7 μg per disk compared to uptake in formula II 58.8. A product with arginine thus has a quick wit that is 79.8% higher than the commercial formulation.

Test against joining. Formula II (decrease by 0.1845) shows results higher than the positive control (triclosan without arginine, decrease by 0.1809) with a light, unexpressed border, and formula I (arginine without triclosan, decrease by 0.1556) with a wider the border. Antibacterial test. Formula II (decrease by 0.1980 reduction) outperforms reliable control (decrease by 0.1789) and formula I (decrease by 0.1891).

Example 4 - Delivery of antibacterial agents in formulations containing precipitated calcium carbonate

Formulations containing 2% arginine bicarbonate were prepared as follows.

Formula A

OUTCOME MATERIAL % WEIGHT Deionized water 32,420 70% sorbitol 23,000 Carboxymethyl cellulose 0.940 Xanthan gum 0.210 Saccharin Sodium 0.450 Sodium silicate 0,800 Bicarbonate of soda 0,500 Arginine Bicarbonate 2,000 Precipitated Calcium Carbonate 36,000 Sodium Monofluorophosphate 0.760 Flavoring 1,000 Triclosan 0,300 Sodium Lauryl Sulfate 1,620 TOTAL AMOUNT 100,000

Formula B

OUTCOME MATERIAL % WEIGHT Deionized water 23,200 70% sorbitol 23,000 Xylitol 2,500 Carboxymethyl cellulose 0.940 Xanthan gum 0.210 Saccharin Sodium 0.450 Sodium silicate 0,800 Bicarbonate of soda 0,500 Arginine Bicarbonate 2,000 Precipitated Calcium Carbonate 42,000 Sodium Monofluorophosphate 1,100 Flavoring 1,000 Triclosan 0,300 Sodium Lauryl Sulfate 2,000 TOTAL AMOUNT 100,000

Formula C

OUTCOME MATERIAL % WEIGHT Deionized water 34,420 70% sorbitol 23,000 Carboxymethyl cellulose 0.940 Xanthan gum 0.210 Saccharin Sodium 0.450 Sodium silicate 0,800 Bicarbonate of soda 0,500 Arginine Bicarbonate 0,000 Precipitated Calcium Carbonate 36,000 Sodium Monofluorophosphate 0.760 Flavoring 1,000 Triclosan 0,300 Sodium Lauryl Sulfate 1,620 TOTAL AMOUNT 100,000

In the capture test described in the above examples, formula A shows 57.86 μg of triclosan on the disk, compared to 22.88 μg with formula C (control without arginine).

Example 5

Mouthwash Formulation

The mouthwash formulations of the present invention were made using the following components.

Fluid with triclosan rinse with arginine

OUTCOME MATERIAL % WEIGHT Deionized water q.s. Glycerol 15,000 Sodium methyl cocoyl taurate 0.250 95% ethanol 6,000 Sodium Lauryl Sulfate 0,200 Allantoin 0,110 Sodium benzoate 0,100 Sodium salicylate 0,100 Sodium fluoride 0,050 Saccharin Sodium 0.005 Triclosan 0,030 Phosphoric Acid 85% 0,120 L-arginine 0,300 Flavoring 0,100 Dye 0.001 PVM / MA 0.250 TOTAL AMOUNT 100,000 PH level 7.0

Example 6

Toothpaste Formulation Containing Precipitated Calcium Carbonate (PAC)

A group of testing consumers trained to test the sensory characteristics of toothpaste formulations used different toothpaste formulations, which were used under double-blind consumer testing, copying the use of toothpaste by consumers.

The group was asked to traditionally use toothpaste of different formulations and then evaluate various sensory characteristics. For the main toothpaste formulation containing precipitated calcium carbonate (PAC), the known formulation served as a placebo control and the corresponding formulations were also tested, additionally containing 1, 2, 3 or 5% by weight of arginine bicarbonate. It was unexpectedly revealed that PAC formulations containing arginine bicarbonate showed an increase in consumer acceptance due to aroma intensity, cooling properties and ease of foaming, and, in addition, formulations additionally containing 2% by weight of arginine bicarbonate showed an increase in overall positive rating when generally liked taste, taste when cleaning and taste after cleaning. Additionally, formulations additionally containing arginine bicarbonate were perceived significantly better than the placebo control for all reflected characteristics, including perceived effectiveness, a feeling of cleanness in the mouth / teeth, product acceptability, taste and overall product quality.

On the other hand, when testing formulations based on dicalcium phosphate, rather than based on precipitated calcium carbonate (PAC), it was noted that the addition of arginine bicarbonate does not show significantly improved sensory characteristics compared to a similar formulation without the addition of arginine bicarbonate.

This example shows that the addition of a basic amino acid, such as arginine, especially in the form of bicarbonate, can unexpectedly enhance the sensory characteristics of toothpaste formulations, to the greatest extent with a formulation based on precipitated calcium carbonate (PAC), when used in an oral composition cavity of the present invention.

Example 7

Essential amino acids other than arginine

The S. sanguis culture was incubated overnight at 37 ° C in trypticase-soy broth (Becton Dickinson. Sparks, MD). The culture was centrifuged at 5000 rpm for 5 minutes in a single amount of 1 milliliter in pre-weighed tubes to collect about 5 milligrams of wet debris weight. The debris was then resuspended in 20 mmol potassium phosphate buffer (JT Baker, Phillipsburg, NJ) at pH 4.0 to simulate a stressful environment for the bacterial cell that will produce ammonia for survival. The final concentration was 5 milligrams per milliliter. To this final concentration was added L-arginine, L-citrulline or L-orinitin at a final concentration of 5 mmol together with a final concentration of 0.1% sucrose (VWR. West Chester. PA). Before determining the ammonia production, this mixture was incubated at 37 ° C in a water bath with a shaker for 30 minutes.

For ammonia analysis, an ammonia test kit from Diagnostic Chemicals Limited (Oxford, CT) was used. The indicated kit is intended for in vitro quantitative analysis of plasma ammonia, but the procedure was modified to determine and quantify the production of ammonia in plaque and / or bacteria.

The table below shows the ammonia production values in 6 separate trials using S. sanguis at pH 4.0, as described above. The results confirm that the intermediates produced by the arginine deiminase system can be used to generate ammonia for cell survival.

This example shows that basic amino acids other than arginine efficiently produce ammonia in the oral cavity and thus increase the pH level of plaque when used in the oral composition of the present invention.

Claims (11)

1. Composition for caring for the oral cavity, containing:
arginine, in free form or in salt form in an amount of from 0.1 to 20 wt.% of the total weight of the composition;
triclosan in an amount of from 0.01 to 5 wt.% of the total weight of the composition,
an anionic polymer, which is a copolymer of methyl vinyl ether and maleic anhydride,
anionic surfactant in an amount of from 0.01 to 10 wt.% of the total weight of the composition,
soluble fluoride salt in an amount of from 0.01 to 2 wt.% of the total weight of the composition, or a fluoride ion source in an amount to provide 50-25000 ppm of fluoride ion weight, in which a soluble fluoride salt or fluoride ion source is selected from sodium fluoride, sodium monofluorophosphate and mixtures thereof, and
abrasive material, which contains a fraction of small particles comprising at least about 5 wt.% of the total weight of the composition, and in said fraction small particles have an average diameter d50 of less than 5 μm. 2. The composition according to claim 1, in which the fraction of small particles optionally comprises at least about 20 wt.% Of the total weight of the composition. 3. The composition according to claim 1, in which the arginine salt is selected from arginine phosphate, arginine bicarbonate and arginine hydrochloride. 4. The composition according to claim 1, in which triclosan is present in an amount of from 0.01 to 1 wt.% Of the total weight of the composition. 5. The composition according to claim 1, containing anionic surfactant in an amount of from 0.3 to 4.5 wt.% Of the total weight of the composition, in which the anionic surfactant is optionally selected from sodium lauryl sulfate, sodium laureth sulfate, and mixtures thereof. 6. The composition according to claim 1, in which the abrasive material is selected from calcium carbonate, silicon dioxide and mixtures thereof, or the material in the form of particles is selected from silicon dioxide and calcium carbonate. 7. The composition according to claim 1, which is a toothpaste. 8. The composition according to claim 7, additionally containing xylitol. 9. The composition according to claim 1, in which the abrasive wear of dentin by the radioactive method (RDA) is less than about 150. 10. The composition according to claim 1 in the form of a toothpaste, which further comprises one or more components of: water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, moisturizers, thickeners, antibacterial agents, preservatives, flavorings, colorants and / or combinations thereof. 11. The use of the composition according to any one of claims 1 to 10 for the care of the oral cavity with the aim of:
a. reduce or inhibit the formation of dental caries,
b. reduction, restoration or inhibition of early enamel damage,
c. reduce or inhibit demineralization and accelerate remineralization of teeth,
d. reduce tooth sensitivity
e. reduce or inhibit gingivitis,
f. promoting the healing of ulcers and wounds in the oral cavity,
g. reduce the number of bacteria that produce acid,
h. increase in the relative content of arginolytic bacteria,
i. prevent the formation of microbial biofilms in the oral cavity,
j. increasing and / or maintaining after sugar loading the pH value of the plaque at least at a pH of 5.5,
k. reduce plaque formation,
n strengthening overall health, including cardiovascular health, for example, by reducing the possibility of general infection through the tissues of the oral cavity,
R. formation of resistance or protection of teeth against cariogenic bacteria; and / or
q. brushing your teeth and mouth.