RU2615370C2 - Oral composition containing micro-aggregates - Google Patents

Abstract

FIELD: hygiene.

SUBSTANCE: group of inventions relates to antimicrobial micro-aggregates, methods of their production and use, as well as oral care compositions containing such micro-aggregates. Proposed antimicrobial micro-aggregate includes a zinc oxide particle stabilised with a nonionic surfactant and coated with polymer, where polymer is a hydroxypropyl methylcellulose, wherein average size of micro-aggregate ranges from 5 to 50 micron in main dimension. To obtain a plurality of said micro-aggregates, method includes mixing a coating polymer, which is a hydroxypropyl methylcellulose, zinc oxide and surfactant in a suitable solvent or carrier, spray drying mixture and separating obtained micro-aggregates, having average size of micro-aggregate from 5 to 50 micron in main dimension. Also disclosed is an oral care composition containing such micro-aggregates, method of inhibiting accumulation of dental plaque and/or calculus, involving contacting oral surface with said composition.

EFFECT: use of group of inventions provides higher antimicrobial action, efficient for slowing down accumulation of dental plaque and/or calculus.

11 cl, 4 tbl, 1 ex

Description

The present invention relates to oral care compositions for use in the oral cavity to slow the accumulation of plaque and / or tartar. The invention provides composites containing microaggregates of particles with respect to an insoluble metal, metal salt or metal oxide, for example zinc oxide, stabilized with a surfactant and coated with a polymer, and the use of such particles in methods of delaying the accumulation of plaque and / or tartar.

BACKGROUND OF THE INVENTION

Plaque forms in the form of a film on the teeth. It is a product of the growth of microbes, and is a dense microbial layer consisting of a mass of microorganisms included in the matrix, which accumulates on the tooth surfaces. Microorganisms are mainly coccidia-related microorganisms, especially in early plaque, which, in the mouth of some people, change to filamentous microorganisms in at least a few days.

Plaque, as observed, is formed after prophylactic treatment of the teeth due to bacteria that grow from defects in tooth enamel, where they are alive and left unaffected by the prophylactic treatment. Plaque can form on any part of the tooth surface, and it is especially often present on the edge of the gums, in enamel cracks and on the surface of tartar. The importance of examining the effects of plaque on teeth is based on the tendency of plaque to provoke gingivitis and possibly other types of periodontal disease, as well as dental caries and tartar growth. Plaque is a precursor to tartar. The latter is formed from plaque, which accumulates on the teeth in the form of solid mineralized deposits. This is especially the case with the appearance of formations on the edge of the gums, that is, at the junction of the tooth and gums. Both bacterial and non-bacterial components of plaque are mineralized and they form tartar, which includes, in addition to mineralized bacteria, organic components such as epithelial cells, living bacteria, saliva proteins, white blood cells, and crystals of substances having molecular bound calcium and phosphorus, for example, hydroxyapatite, octacalcium phosphate, brushite and vitlokite. Tartar, like plaque, is considered the main factor and cause of periodontal disease.

Therapeutic compositions have been described comprising, in the composition of polymer particles, metal oxides, including zinc oxide. For example, U.S. Pat. 6368586 discloses methods and compositions in which metal oxides, including zinc oxide, are included in polymer microaggregates that contain a therapeutic component in order to increase the adhesion of the therapeutic polymer to the surface of the mucous membrane. Spray drying and some other alternative ways of producing polymer / metal oxide particles are disclosed. U.S. Patent No. 7691413 describes composite particles containing a polyolefin resin having a crystallization degree of 80% or less and zinc oxide, which are obtained by hot microencapsulation by melting or cold microencapsulation by spraying, a method for producing composite particles and cosmetics containing such composite particles.

Zinc oxide and zinc salts are known to be useful components in oral care products. For example, U.S. Pat. No. 5,486,350 describes zinc compounds, including zinc oxide, among the list of compounds acting against hard deposits and tartar, useful for use in toothpaste. Zinc oxide was also dispersed in a polymer matrix, which was cast in the form of a film and divided into strips for inclusion in oral care compositions. This is an incentive to include zinc oxide in oral care products, however, it should be borne in mind that particles tend to agglomerate and precipitate from the drug (zinc oxide is practically insoluble in water) and / or react with other components .

SUMMARY OF THE INVENTION

The invention provides, in one embodiment, oral care compositions comprising microaggregates that include small particles of a relatively insoluble metal, metal salt or metal oxide, for example zinc oxide, stabilized with a surfactant and coated with a polymer, providing increased dental control stone and plaque.

In one embodiment, particles of a substantially insoluble metal, metal salt, or metal oxide, in particular zinc oxide, having an average diameter of 0.1-10 microns, for example 0.2-2 microns, for example about 1.4 microns , with an average surface area equal, in particular, 0.1-10 m ² / g, for example, 0.5-5 m ² / g, for example, approximately 0.7 m ² / g, are agglomerated into microaggregates with surfactant substance and polymer. Microaggregates are formations larger than 5 microns, for example, more than 20 microns, but less than 50 microns. They are formed, for example, by mixing particles of a metal or metal oxide with a surfactant and a polymer in the presence of a solvent, followed by drying, for example, spray drying. The surfactant is preferably a nonionic surfactant, for example polyoxyethylene sorbitan monooleate (for example, one of the Tween compounds, for example Tween 80, or polyethoxylated tocopherol, for example D-alpha tocopherol succinate - PEG 1000), which prevents particle aggregation and supports individual particle size. The polymer is preferably a water-soluble polymer or a mixture of polymers selected on the basis of solubility properties, which are primarily a function of chemical composition and molecular weight. The polymer is preferably soluble in saliva, releasing particles of metal or metal oxide, but it is resistant to compounds present in oral care preparations such as toothpaste, in particular glycerol, sorbitol and a small amount of water. When used, coated particles break down and release metal particles, metal salts or metal oxide onto the surface of the tooth and gums.

In a further embodiment of the invention, methods are provided for delaying the accumulation of plaque and / or tartar using the preparations of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention, in a first embodiment, provides microaggregates comprising particles of a substantially insoluble metal, metal salt or metal oxide stabilized with a surfactant coated with a polymer, for example microaggregates, for use in compositions as described below, wherein the polymer is soluble in water, a polymer or a mixture of water soluble polymers.

The invention, in one embodiment, provides a composite comprising microaggregates as part of a formulation with a suitable carrier, for example an oral care composite (Composite 1.0), which contains microaggregates comprising a substantially insoluble metal, metal salt or metal oxide, surface stabilized -active substance and coated with a polymer, and a carrier, for example, the following.

1.0.1. Composite 1.0, where the microaggregates are obtained by spray drying a mixture of particles, surfactant and polymer in a solvent, for example, in an aqueous solvent, for example, selected from water and aqueous ethanol.

1.0.2. Any of the preceding composites where the substantially insoluble metal, metal salt or metal oxide is selected from zinc oxide, tin dioxide, calcium fluoride, titanium dioxide and mixtures thereof.

1.0.3. Any of the preceding composites wherein the substantially insoluble metal, metal salt or metal oxide is zinc oxide.

1.0.4. Any of the preceding composites where a substantially insoluble metal, metal salt or metal oxide has a solubility in water of less than 1 mg / 100 ml at 30 ° C.

1.0.5. Any of the preceding composites wherein the surfactant is a nonionic surfactant.

1.0.6. Any of the preceding composites wherein the surfactant is selected from a polyoxyethylene sorbitan fatty acid acyl ester, a polyoxyethylene sorbitan fatty acid ester of a polyoxyethylene sorbitan fatty acid monoacyl ester, a polyoxyethylene sorbitan diacyl fatty acid ester or a polyoxyethylene ether thereof, for example, and a fatty ester thereof, for example as polyoxyethylene sorbitan monooleates (e.g., Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65 or Polysorbate 80, Specifically, polysorbate 80, for example polyoxyethylene (20) sorbitan monooleate such as Tween 80) or polietilenglikoltokoferolsuktsinaty (TPGS, for example, D-alpha-tocopherol succinate - PEG 1000), or mixtures thereof.

1.0.7. Any of the preceding composites, wherein the polymer is a water soluble polymer.

1.0.8. Any of the preceding composites, where the polymer is a mucoadhesive polymer.

1.0.9. Any of the preceding composites, where the polymer is a cellulose ether.

1.0.10. Any of the preceding composites wherein the polymer is hydroxypropyl methylcellulose.

1.0.11. Any of the previous composites, where the average size of microaggregates is from 1 micron to 50 microns in the main dimension.

1.0.12. Any of the previous composites, where the average size of microaggregates is more than 5 microns in the main dimension.

1.0.13. Any of the previous composites, where the average size of microaggregates is more than 20 microns in the main dimension.

1.0.14. Any of the previous composites, where the average size of microaggregates is from 5 microns to 30 microns in the main dimension.

1.0.15. Any of the preceding composites where microaggregates have a size from 10 microns to 25 microns in the main dimension.

1.0.16. Any of the previous composites, where microaggregates are predominantly spherical in shape and have a size of 20 microns in the main dimension.

1.0.17. Any of the preceding composites, where microaggregates are aggregates of particles of zinc oxide with polysorbate and cellulose ether.

1.0.18. Any of the preceding composites, where the particles of a substantially insoluble metal, metal salt or metal oxide, for example zinc oxide, have a size of 0.1-10 microns, for example, 0.2-2 microns, for example, about 1 micron in average diameter.

1.0.19. Any of the preceding composites, where the particles of a substantially insoluble metal, metal salt or metal oxide have an average surface area of 0.1-10 m ² / g, for example, 0.5-5 m ² / g, for example, approximately 1, 4 m ² / g.

1.0.20. Any of the preceding composites, where the particles of a substantially insoluble metal, metal salt or metal oxide have an average size of 1 micron in the main dimension and an average surface area of 1.4 m ² / g.

1.0.21. Any of the preceding composites where the polymer dissolves in saliva after application, but is resistant to compounds found in oral care products, such as toothpaste, for example, it is resistant to glycerol, sorbitol and small amounts of water.

1.0.22. Any of the preceding composites, where the polymer is present in the microaggregate in an amount of 25-50% by dry weight.

1.0.23. Any of the preceding composites, where particles of a substantially insoluble metal, metal salt or metal oxide are present in the composite in an amount of 40-60% by dry weight.

1.0.24. Any of the preceding composites, further comprising a non-polymeric carrier.

1.0.25. Any of the preceding composites, where the microaggregate includes a non-polymer carrier, which is propylene glycol, and is present in the microaggregate in an amount of 5-15% by dry weight.

1.0.26. Any of the preceding composites, where the microaggregate includes:

a. a water-soluble polymer, for example, from among cellulose ethers, for example, HPMC, for example, a mixture of low and high molecular weight HPMC, in an amount of 30-45%;

b. particles of a substantially insoluble metal, metal salt or metal oxide, for example, zinc oxide particles, in an amount of, for example, 40-60%;

c. optionally, a non-polymeric carrier, for example propylene glycol, in an amount of, for example, 5-15%;

d. non-polar surfactant, for example, polysorbate, for example, polysorbate 80, in an amount of, for example, 0.5-1%;

e. optionally an anti-foaming agent, for example, a silicone emulsion, in an amount of, for example, 0.01-0.02%.

1.0.27. Any of the preceding composites where zinc-based material is present in an amount effective to delay, inhibit or control plaque formation with regular use.

1.0.28. Any of the preceding composites, where microaggregates are present in an amount of from 0.1 to 10%, from 1 to 7.5% by weight, of the total weight of the composition, for example, 1% or 1.5%, 3.75%, 5% or 7.5% by weight, of the total weight of the composition.

1.0.29. A composite obtained or obtained by combining the components indicated for any of the previous composites.

The invention also provides oral care compositions, for example, the following.

1.1.1. Oral care compositions comprising composites with the characteristics indicated in any of the previous composites.

1.1.2. Any of the preceding compositions, further comprising an abrasive material.

1.1.3. The composition indicated as the previous embodiment, where the abrasive material is selected from sodium bicarbonate, calcium phosphate (e.g. dicalcium dihydrogen phosphate), calcium sulfate, precipitated calcium carbonate, silicon oxide (e.g. hydrated silicon oxide), iron oxide, alumina, perlite, plastic particles, for example, polyethylene particles, and combinations thereof.

1.1.4. Any of the preceding compositions, further comprising an effective amount of an antibacterial agent.

1.1.5. A composition as indicated in the previous embodiment, wherein the antibacterial agent is selected from halogenated diphenyl ether (e.g. triclosan), plant extracts and essential oils (e.g. rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, ginokitol, catechin, salicylic acid methyl ester, epigallocatechin gallate, epigallocatechin, gallic acid, miswack extract, sea buckthorn extract), bisguanidine antiseptics (e.g. chlorhexidine, alexidine il and octenidine), quaternary ammonium compounds (e.g. cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecyl-4-ethylpyridinium chloride (TDEPC)), phenolic antiseptics, hexetidine, sanvinidine, octovenidine , delmopinol, saliflora, metal ions other than zinc (e.g., tin salts, copper salts, iron salts), sanguinarine, propolis, oxidizing agents (e.g. hydrogen peroxide, buffered peroxyborate or sodium peroxycarbonate), phthalic acid and its salts, monopertal acid her sol esters, ascorbyl stearate, oleoylsarcosine, alkyl sulfate, dioctyl sulfosuccinate, saliuyl anilide, domifenbromide, delmopinol, octapinol and other piperidine derivatives, nisine-based preparations, and chlorite salts; and mixtures of any of the listed substances.

1.1.6. The composition indicated as the previous embodiment, wherein the antibacterial agent is triclosan.

1.1.7. Any of the preceding compositions comprising arginine, in a free or orally acceptable salt form, for example, arginine hydrochloride or arginine bicarbonate.

1.1.8. Any of the preceding compositions, further comprising a soluble fluoride salt.

1.1.9. The composition indicated as the previous embodiment, wherein the soluble fluoride salt is selected from tin fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride (e.g., N'-octadecyltrimethylenediamine-N, N, N'-tri 2-ethanol) -dihydrofluoride), ammonium fluoride, titanium fluoride, hexafluorosulfate, and combinations thereof.

1.1.10. The composition indicated as any of the two previous options, where the fluoride salt is present in an amount of from 0.1 to 2%, for example, 1.1% by weight, of the total weight of the composition.

1.1.11. Any of the preceding compositions, further comprising a non-zinc based anti-tartar agent, for example polyphosphate, for example pyrophosphate, tripolyphosphate or hexametaphosphate, for example, in the form of a sodium salt.

1.1.12. Any of the preceding compositions comprising at least one surfactant.

1.1.13. Any of the preceding compositions comprising at least one surfactant selected from sodium lauryl sulfate, cocamidopropyl betaine, and combinations thereof.

1.1.14. Any of the preceding compositions comprising an anionic surfactant, for example, selected from sodium lauryl sulfate, sodium laureth sulfate, and mixtures thereof.

1.1.15. Any of the previous compositions, including sodium lauryl sulfate in an amount of from 0.5 to 3% by weight of the composition.

1.1.16. Any of the preceding compositions comprising at least one humectant.

1.1.17. Any of the preceding compositions comprising at least one humectant selected from glycerol, sorbitol, and combinations thereof.

1.1.18. Any of the preceding compositions comprising at least one liquid polymer carrier, for example, selected from polyethylene glycols, copolymers of polyvinyl methyl ether and maleic acid, polysaccharides (for example, cellulose derivatives, for example carboxymethyl cellulose or polysaccharide resins, for example xanthan gum or carrageenan resin) .

1.1.19. Any of the previous compositions, including strips or fragments of resin.

1.1.20. Any of the preceding compositions comprising a flavoring, flavoring and / or coloring agent.

1.1.21. Any of the preceding compositions comprising water.

1.1.22. Any of the preceding compositions comprising an anti-inflammatory compound, for example, an inhibitor of at least one of the pro-inflammatory host factors selected from a matrix of metalloproteinases (MMP), cyclooxygenases (COX), PGE2, interleukin 1 (IL-1), an enzyme that transforms IL-β (ICE), transforming growth factor β1 (TGF-β1), inducible nitric oxide synthase (iNOS), hyaluronidase, cathepsins, nuclear factor capa B (NF-κB) and kinase associated with IL-1 receptor (IRAK), for example selected from aspirin, keterolac, flurbiprofen, ibuprofen, for example hay, indomethacin, aspirin, ketoprofen, piroxicam, meclofenamic acid nordigidrogvayaretovoy acid and mixtures thereof.

1.1.23. Any of the preceding compositions comprising an antioxidant, for example, selected from the group consisting of Coenzyme Q10, PQQ, Vitamin C, Vitamin E, Vitamin A, Anethole Dithiotion and mixtures thereof.

1.1.24. Any of the previous compositions including triclosan.

1.1.25. Any of the previous compositions, including triclosan in an amount of from 0.01 to 1% by weight, of the total weight of the composition.

1.1.26. Any of the previous compositions, including triclosan in an amount of 0.3% by weight, of the total weight of the composition.

1.1.27. Any of the preceding compositions comprising a tooth whitening agent.

1.1.28. Any of the preceding compositions comprising a tooth whitening agent selected from an active whitener selected from the group consisting of peroxides, metal chlorites, perborates, precarbonates, peroxyacids, hypochlorites, and combinations thereof.

1.1.29. Any of the preceding compositions, further comprising a hydrogen peroxide or a source of hydrogen peroxide, for example, urea peroxide, or a peroxide salt or complex (for example, salts of peroxyphosphate, peroxycarbonate, perborate, peroxysilicate or persulfate; for example, calcium peroxyphosphate, sodium perborate, sodium percarbonate, sodium peroxyphosphate and potassium persulfate), or complexes of polymers and hydrogen peroxide, such as a polymer complex of polyvinylpyrrolidone and hydrogen peroxide.

1.1.30. Any of the preceding compositions, further comprising a source of calcium and phosphate selected from (i) calcium glass complexes, e.g., sodium / calcium phosphosilicates, and (ii) calcium / protein complexes, e.g., casein phosphopeptide / amorphous calcium phosphate.

1.1.31. Any of the preceding compositions, further comprising a soluble calcium salt, for example, selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.

1.1.32. Any of the preceding compositions, further comprising an agent that inhibits or prevents the deposition of bacteria, for example, solbrol or chitosan.

1.1.33. Any of the preceding compositions, further comprising a physiologically acceptable potassium salt, for example, potassium nitrate, potassium citrate or potassium chloride, in an amount effective to reduce tooth sensitivity.

1.1.34. Any of the preceding compositions effective for use in the oral cavity, for example, for brushing teeth, which (i) reduces or inhibits the formation of dental caries, (ii) reduces, restores or inhibits precary enamel lesions detected, for example, by quantitative light-induced fluorescence (QLF) ) or by electric caries measurement (ECM), (iii) reduces or inhibits demineralization and promotes remineralization of teeth, (iv) reduces hypersensitivity of teeth, (v) reduces or inhibits gingivitis, (vi) promotes healing of wounds or cuts in the oral cavity, (vii) reduces the levels of acids produced by bacteria, (viii) increases the relative levels of arginolytic bacteria, (ix) inhibits the formation of microbial biofilms in the oral cavity, (x) raises and / or maintains the pH value of plaque by levels corresponding to at least 5.5 after sugar provocation, (xi) reduces plaque accumulation, (xii) reduces dry mouth, (xiii) cleans teeth and oral cavity (xiv) reduces erosion, (xv) whitens teeth, and / or (xvi) immunize teeth against cariogenic bacteria.

1.1.35. Any of the preceding compositions further comprising an antifoam agent.

1.1.36. Any of the preceding compositions, wherein the composition is a toothpaste.

1.1.37. Any of the previous composites, where the composition is a toothpaste, optionally additionally comprising one or more of water, abrasives, surfactants, blowing agents, vitamins, polymers, enzymes, moisturizers, thickeners, antimicrobials, preservatives, flavoring agents, coloring agents and / or combinations thereof.

1.1.38. Any of the preceding composites, which is a toothpaste containing microaggregates, which include particles of zinc oxide, where the agglomerates have an average size of 5 to 50 microns in the main dimension, individual particles have an average size of 1 micron in the main dimension, the average surface area equal to 1.4 m ² / g, and a polymer coating of microaggregates, including hydroxypropyl methylcellulose, is spray dried.

1.1.39. A composition obtained or obtained by combining the components that are indicated for any of the previous compositions.

The invention also provides methods, in particular the following.

1.2.1. A method for delaying the accumulation of plaque and / or tartar, comprising contacting the surfaces of the oral cavity with composites comprising microaggregates that include particles of a substantially insoluble metal, metal salt or metal oxide stabilized with a surfactant and coated with a polymer, for example, using any from the preceding compositions 1.0 and further, for example, by brushing your teeth and gums with a composition comprising microaggregates.

1.2.2. A method that (i) reduces or inhibits the formation of dental caries, (ii) reduces, restores or inhibits precarious enamel lesions detected, for example, by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), (iii) reduces or inhibits demineralization and promotes remineralization of teeth, (iv) reduces tooth hypersensitivity, (v) reduces or inhibits gingivitis, (vi) promotes the healing of wounds or cuts in the oral cavity, (vii) reduces the levels of acids produced by bacteria and, (viii) increases the relative levels of arginolytic bacteria, (ix) inhibits the formation of microbial biofilms in the oral cavity, (x) raises and / or maintains a pH of plaque at levels corresponding to at least 5.5 after sugar provocation, (xi) reduces plaque accumulation, (xii) reduces dry mouth, (xiii) cleans teeth and oral cavity (xiv) reduces erosion, (xv) whitens teeth, and / or (xvi) immunizes teeth against cariogenic bacteria, including contacting oral surfaces with microaggregates including essentially particles of an insoluble metal, metal salt or metal oxide stabilized with a surfactant and coated with a polymer, for example, using any of the preceding compositions 1.0 and further

1.2.3. A method of producing microaggregates comprising particles of a substantially insoluble metal, metal salt or metal oxide stabilized with a surfactant and coated with a polymer, comprising mixing the components described above, for example, by mixing the following components:

a. a water-soluble polymer, for example from among cellulose ethers, for example, HPMC, for example, a mixture of low and high molecular weight HPMC, in an amount of 30-45%;

b. particles of a substantially insoluble metal, metal salt or metal oxide, for example zinc oxide particles, in an amount of, for example, 40-60%;

c. a non-polar surfactant, for example, polysorbate 80, in an amount of, for example, 0.5-1%;

d. non-polymeric carrier, for example, propylene glycol, in an amount of, for example, 5-15%;

e. optionally an anti-foaming agent, for example, a silicone emulsion, in an amount of, for example, 0.01-0.02 with a suitable solvent or carrier, for example, water and / or ethanol;

spray drying the mixture; and

the allocation of microaggregates obtained in this way.

A composite is also provided according to any one of paragraphs. 1-6 of the claims, or a composition according to any one of paragraphs. 7 and 8 of the claims, for use to delay the accumulation of plaque and / or tartar.

In one embodiment of the invention, particles of a substantially insoluble metal, metal salt or metal oxide, for example zinc oxide powder, are mixed with various coating solutions using continuous mixing to obtain a homogeneous suspension suitable for pumping and spraying. The coating solution may contain polymers, cosolvents, surfactants, dispersing agents, salts or other additives to facilitate the implementation of the method.

Polymers: Polymers useful for coating aggregates of zinc particles generally include any of the polymers commonly used in oral care compositions, as discussed below. In one embodiment, mucoadhesive polymers are preferred since they can increase the effective contact time between particles and oral tissues. For example, hydrophilic polymers or hydrogels can be used in microaggregates. Among a large class of hydrophilic polymers, polymers that contain carboxyl groups and which exhibit better mucoadhesive properties are the following: polyvinylpyrrolidone (PVP), methyl cellulose (MS), sodium carboxymethyl cellulose (SCMC) hydroxypropyl cellulose (HPC), and other cellulose derivatives such as hydroxypropyl (HPMC). Hydrogels are a class of polymer biomaterials that swell due to absorbed water, interact by adhesion with mucous membranes that are coated with an epithelium, in particular polymers with an anionic group, which are Carbopol, polyacrylates and their cross-linked modifications; with a cationic group - chitosan and its derivatives; or with a neutral group - Eudragit-NE30D, etc.

Thus, the oral care compositions of the invention may include one or more polymers, such as polyethylene glycol, copolymers of polyvinyl methyl ether and maleic acid, polysaccharides (for example, cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide resins, for example xanthan gum or carrageenan gum) . Acidic polymers, for example polyacrylate gels, can be provided in the form of their free acids, or in the form of partially or completely neutralized with an aqueous solution of an alkali metal (e.g. potassium and sodium) or an ammonium salt. Certain embodiments include copolymers (1: 4 to 4: 1) of maleic anhydride or acid with another polymerizable ethylenically unsaturated monomer, for example methoxyethylene methyl vinyl ether, with a molecular weight (MW) of 30,000 to 1,000,000. These copolymers are available, for example, as Gantrez AN 139 (MW 500,000), AN 119 (MW 250,000) and S-97 (MW 70,000) pharmaceutical grade, from GAF Chemicals Corporation.

Other suitable polymers include, for example, a copolymer (1: 1) of maleic anhydride with ethyl acrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone or ethylene, the latter being available, for example, as Monsanto EMA No.1103, M.W. 10000, and as EMA Grade 61, and a copolymer (1: 1) of acrylic acid with methyl methacrylate or hydroxyethyl methacrylate, methyl acrylate or ethyl acrylate, isobutyl vinyl ether or N-vinyl-2-pyrrolidone.

In general, polymerizable olefinically unsaturated or ethylenically unsaturated carboxylic acids containing an activated carbon-carbon double olefinic bond and at least one carboxylic acid group, i.e., an acid containing a double olefinic bond that c easily acts upon polymerization due to its presence, are generally suitable. in the monomer molecule in the alpha-beta position relative to the carboxyl group, or as part of the terminal methylene group. Illustrative examples of such acids are acrylic, methacrylic, ethacrylic, alpha-chloroacrylic, crotonic, beta-acryloxypropionic, sorbic, alpha-chlorosorbic, cinnamon, beta-styrylacrylic, muconic, itaconic, citraconic, mesaconic, glutacenyl, glutacenyl 2-benzyl acrylic, 2-cyclohexyl acrylic, angelic, umbella, fumaric, maleic acids and their anhydrides. Other various olefin monomers capable of copolymerization with such carboxylic monomers include vinyl acetate, vinyl chloride, dimethyl maleate, and the like. The copolymers contain a sufficient amount of carboxyl salt groups for their solubility in water.

An additional class of polymeric agents includes a composition comprising homopolymers of substituted acrylamides and / or homopolymers of unsaturated sulfonic acids and their salts, especially when polymers based on unsaturated sulfonic acids are selected from acrylamidoalkanesulfonic acids, for example, 2-acrylamide-2-methylpropanesulfonic acid having molecular weight 1000 to 2,000,000 described in US Pat. 4842847, dated June 27, 1989 (in the name of Zahid), incorporated herein by reference.

Another useful class of polymeric agents includes polyamino acids, especially those that contain a portion of anionic surface-active amino acids, such as aspartic acid, glutamic acid, and phosphoserine, as disclosed in US Pat. 4,866,161 (addressed to Sikes et al.), Incorporated herein by reference.

Useful polymers include hydrophilic and hydrophobic polymers. In some embodiments of the invention, the polymer is soluble in a solvent such as water. A water-soluble polymer that dissolves during exposure to water and when using physical force during use (for example, while brushing your teeth or cleaning with a brush or pad) is desirable. In some embodiments of the invention, the polymer is not soluble, but it breaks down in water, being dispersible, that is, the polymer disperses into small fragments as a result of applying mechanical or shear forces. In some embodiments of the invention, the polymer is not soluble, but it is capable of swelling. When the polymer does not completely break down during use, it may be a water-repellent polymer or a water-resistant hydrophilic polymer, such as some types of cellulose, for example paper. Examples of useful polymers are described in US Pat. 4713243 (in the name of Schiraldi et al.), No. 6419903, No. 6419906, No. 6514483 (all in the name of Xu), and No. 6669929 (in the name of Boyd et al.); U.S. Patent Publication No. 2004/0126332, No. 2004/0136924 and No. 2004/0042976 (all in the name of Boyd et al.) And No. 2004/0062724 (addressed to Moro et al.).

Preferably, the polymers are selected to provide at least one of the following: (1) the desired stability of the microparticles in the carrier, (2) the desired rate of disintegration of the polymers during use of the composition, or (3) the desired level of exposure to particles during use of the composition.

In preferred embodiments of the invention, the polymer coating is water soluble and includes, for example, a water soluble polymer, a water dispersible polymer or a water insoluble polymer with an optional water soluble filler. The relative amounts of a water-insoluble polymer, a water-soluble polymer or an optional water-soluble filler can be selected based on the amount of active ingredient released, and depending on how intensively or for how long the composition will be used, for example for brushing teeth, for cleaning or other mechanical impact that occurs during use of the aqueous composition.

In a specific embodiment, the water-soluble polymer is a cellulose ether polymer such as hydroxyalkylalkyl cellulose, including hydroxypropyl methyl cellulose (HPMC), commercially available from Dow Chemical Company, Midland, Mich., USA, in the form of products called METHOCEL®, including, for example, METHOCEL® E5, METHOCEL® E5 LV, METHOCEL® E50, METHOCEL® E15, and METHOCEL® K100, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), methyl cellulose (MS), carboxymethyl cellulose (CMC), and mixtures thereof. Other useful polymers include polyvinylpyrrolidone (PVP), which can have an average molecular weight of 100,000 or more and up to 1.5 million, vinyl acetate, copolymers of vinyl acetate and polyvinylpyrrolidone, such as KOLLIDON® VA64 (available from BASF, 60:40 by weight vinylpyrrolidone) and PLASDONE® S630 PVP (available from International Specialty Products, Wayne, NJ, USA, 60:40 by weight of vinylpyrrolidone: vinyl acetate), ethylene oxide grafted PVA copolymers such as KOLLICOAT® IR (available from BASF, 75%, by weight of PVA, 25% by weight of grafted polyethylene glycol), polyvinyl alcohol (PVA), acrylic you and polyacrylic acid, including polyacrylate polymer, crosslinked polyacrylate polymer, crosslinked polyacrylic acid (e.g. CARBOPOL®), vinyl caprolactam / sodium acrylate polymers, methacrylates, maleic polyacrylate acrylate amide polymer, e.g. maleic acid amide acid, e.g. , poly (2-acrylamido-2-methylpropanesulfonate), terpolymers of acrylomethylpropylsulfonic acid / methacrylate / styrene monomers, styrene phosphonate polymers, polyethylene phosphonate, polybutenphos Onat, polystyrene, polyvinyl phosphonates, polyalkylenes, polyalkylene oxides, including polyethylene oxide, i.e., polyethylene glycol, and a carboxyvinyl polymer. It will be appreciated by those skilled in the art that film coatings may also include derivatives, copolymers, and further mixtures of such polymers.

The polymer may include a mixture of water-soluble and water-insoluble polymers, provided that particles are released upon use. Useful water insoluble polymers include polymers soluble in at least one organic solvent; for example, acrylic copolymers (where carboxylic acid was functionalized but not neutralized), cross-linked polyvinylpyrrolidone, for example KOLLIDON® CL or CL-M available from BASF, poly (vinyl acetate) (PVA), some cellulose derivatives such as cellulose acetate, nitrocellulose, alkyl celluloses such as ethyl cellulose, butyl cellulose and isopropyl cellulose, cellulose acetate phthalate, shellac, ethylene vinyl acetate copolymers, vinyl acetate homopolymers, silicone polymers (e.g. dimethyl silicone), polymethyl methacrylate (PMMA), polymer Insoluble organic solvents such as cellulose, polyethylene, polypropylene, polyesters, polyurethane and nylon, natural or synthetic rubber, and mixtures thereof. An example of a suitable film-forming acrylic copolymer is LUVIMER® 30E, a 30% by weight solution of a tert-butyl acrylate / ethyl acrylate / methacrylic acid copolymer in ethanol, commercially available from BASF (Florham Park, N.J., USA). Water-insoluble polymers can be obtained in the form of a dispersion (for example, by emulsion polymerization) and can be stabilized with suitable emulsifiers. One useful PVA emulsion is, for example, KOLLICOAT® SR 30D, a 30% dispersion by weight of PVA in water, stabilized with 2.7% PVP and 0.3% sodium lauryl sulfate by weight. An example of a dispersion of an acrylic copolymer is KOLLICOAT® EMM 30D, a 30% by weight aqueous dispersion of an ethyl acrylate: methyl methacrylate copolymer (ethyl acrylate to methyl methacrylate weight ratio is approximately 2 to 1) with a stated average molecular weight of 800,000 from BASF.

Other useful polymers or water soluble excipients include, but are not limited to, natural resins such as sodium alginate, carrageenan, xanthan gum, acacia gum, gum arabic, guar gum, pullulan, agar, chitin, chitosan, pectin, karaya gum, zein, proudine , oliadin, locust bean gum, tragacanth and other polysaccharides; starches such as maltodextrin, amylose, higher amylose starch, corn starch, potato starch, rice starch, tapioca starch, pea starch, sweet potato starch, barley starch, wheat starch, modified starch starch, for example, starch wax, , dextrin, levan, elsinan and gluten; as well as proteins such as collagen, isolated whey protein, casein, milk protein, soy protein, keratin and gelatin. The coating polymer may also include dispersible or swellable fillers, such as modified starch, alginate esters, divalent or polyvalent ionic alginate salts.

In addition, non-limiting examples of water-insoluble polymers include cellulose acetate, nitrocellulose, ethylene vinyl acetate copolymers, vinyl acetate homopolymer, ethyl cellulose, butyl cellulose, isopropyl cellulose, shellac, hydrophobic silicone polymer (e.g. dimethylsilicon), acetate methyl acetate, and cellulose methyl acetate; ; organic solvent insoluble polymers such as cellulose, polyethylene, polypropylene, polyesters, polyurethane and nylon.

Relative amounts of a water-soluble polymer and a water-insoluble and / or partially water-soluble polymer for coating in an aqueous composition, preferably those that provide stability to the coating during storage of the aqueous composition, but which decay during use of the composition. In various embodiments of the invention, such a coating comprises a water-soluble polymer, the amount of which is from 0.1 to 90%, from 1 to 80%, from 5 to 70%, from 9 to 50%, or from 10 to 40% by weight of the coating . In addition to, or instead of, water-soluble polymer (s), the coating may include partially water-insoluble or water-swellable polymers in an amount of from 0.1 to 50%, preferably from 1 to 10% by weight of the coating. In various embodiments of the invention, a method for stabilizing hydrophilic coatings in an aqueous environment of a carrier comprises using water-soluble and water-insoluble coating materials that are balanced to provide stability during storage of the product in the carrier, but for decomposition when used in order to release The active ingredient contained in the product.

When preparing a coating solution, appropriate solvents and cosolvents for the selected polymer (s) should be selected based on general knowledge of the art in order to obtain a solution forming a film coating swelling at operating temperatures.

The surfactants used to stabilize particles in microaggregates are preferably nonpolar surfactants, or any surfactant that is capable of inhibiting particle aggregation before the formation of microaggregates or after their use. Thus, suitable polymers include, for example, polyoxyethylene sorbitan fatty acid ether, polyoxyethylene sorbitan fatty alcohol ether, polyhydroxyethylene and monocarboxylic fatty acid ether, polyhydroxyethylene and dicarboxylic fatty acid ether, or polyhydroxyethylene and fatty alcohol ether and mixtures thereof, in particular polyoxyethylene e.g. polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65 or polysorbate 80, e.g. polysorbate 80, e.g. polyoxyethylene (20) sorbitan monooleate, e.g. Emer Tween 80) or polietilenglikoltokoferolsuktsinaty (TPGS, for example, D-alpha-tocopherol succinate - PEG 1000), or mixtures of any of the substances listed number.

Oral Care Preparations: Microaggregates of the invention may be formulated as oral care compositions according to known methods. Toothpaste containing microaggregates is particularly preferred.

Sources of fluoride ions: oral care compositions may further include one or more sources of fluoride ions, for example, soluble fluoride salts. As sources of fluoride ions in the compositions of the invention, a wide variety of soluble fluoride ion source materials can be used. Examples of suitable fluoride ion source materials can be found in U.S. Pat. 3,535,421 (in the name of Briner et al.); U.S. Pat. 4,885,155 (to Parran, Jr. et al.) And U.S. Pat. 3,678,154 (to Widder et al.), Incorporated herein by reference.

Representative sources of fluoride ions 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 certain embodiments of the invention, the source of fluoride ions includes tin fluoride, sodium fluoride, sodium monofluorophosphate, as well as mixtures thereof.

In certain embodiments of the invention, the oral composition of the invention may also contain a source of fluoride ions or a fluorine releasing component in amounts sufficient to provide 25 to 25,000 ppm (ppm) fluoride ions, in generally, at least 500 ppm, for example, from 500 to 2000 ppm, for example, from 1000 to 1600 ppm, for example, 1450 ppm. the acceptable level of fluoride ions will depend on the particular application. In toothpaste for general consumer use, the amount of fluoride ions is usually from 1000 to 1500 ppm, in pediatric toothpaste this value is slightly less. A professional toothpaste or coating may have a fluoride ion level of 5,000, or even 25,000 ppm.

Sources of fluoride ions can be added to the compositions of the invention at a level of from 0.01 to 10% or from 0.03 to 5% by weight of the composition in another embodiment, and in another embodiment, from 0.1 to 1% by mass of the composition. The masses of fluoride salts, which provide the necessary level of fluoride ions, will obviously change taking into account the mass of the counterion in the salt.

When the composition comprises calcium bicarbonate, sodium monofluorophosphate is more preferred than sodium fluoride because of its stability.

Abrasives: microaggregates according to the invention can be included in a toothpaste together with abrasive materials, for example, with natural calcium carbonate, precipitated calcium carbonate, with abrasive calcium phosphate, for example, tricalcium phosphate (Ca ₃ (PO ₄ ) ₂ ), hydroxyapatite (Ca ₁₀ (PO ₄ ) ₆ ⋅ (OH) ₂ ) or dicalcium dihydrogen phosphate (CaHPO ₄ ⋅ 2H ₂ O, also called DiCal) or calcium pyrophosphate, and / or with abrasive silicas, such as precipitated silica having an average particle size of up to 20 microns, in particular Zeodent 115 ^® , marketed by J. M. Huber, with sodium metaphosphate, potassium metaphosphate, aluminum silicate, calcined alumina, bentonite, or with other silicon-containing materials, or combinations thereof.

Foaming Agents: The oral care compositions of the invention may also include a substance to increase the amount of foam generated when cleaning the oral cavity. Illustrative examples of agents that increase the amount of foam include, but are not limited to, polyoxyethylene and certain polymers, including, but not limited to, alginate polymers. Polyoxyethylene can increase the amount and consistency of the foam generated by oral administration due to the carrier component of the present invention. Polyoxyethylene is also commonly known as polyethylene glycol ("PEG") or polyethylene oxide. Polyoxyethylenes suitable for this invention have a molecular weight of from 200,000 to 7,000,000 In one embodiment, the molecular weight is from 600,000 to 2,000,000 and in another embodiment - from 800000 to 1000000. Polyox ^® is a trademark for polyoxyethylene high molecular mass produced by Union Carbide. In one embodiment of the invention, polyoxyethylene may be present in an amount of from 1 to 90%, and in another embodiment, from 5 to 50%, and in another embodiment, from 10 to 20% by weight of a component of the carrier component of the cavity care compositions the mouth of the present invention. The dosage of a blowing agent in an individual oral care composition (i.e., in a single dose) is from 0.01 to 0.9%, from 0.05 to 0.5%, and in another embodiment, from 0 1 to 0.2% by weight.

Surfactants: Another substance that is not necessarily included in the oral composition of the invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants are those that are reasonably stable over a wide range of pH values, and are, for example, anionic, cationic, nonionic or zwitterionic surfactants. Suitable surfactants are described more fully, for example, in US Pat. 3,959,458 (addressed to Agricola et al.); U.S. Pat. 3,937,807 (in the name of Haefele); and U.S. Pat. 4051234 (in the name of Gieske et al.), Which are incorporated herein by reference.

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

In another embodiment, useful cationic surfactants can be broadly defined, within the framework of the present invention, as aliphatic derivatives of quaternary ammonium compounds having one long alkyl chain containing from 8 to 18 carbon atoms and representing lauryltrimethylammonium chloride, cetylpyridinium chloride, cetyltrimethylammonium bromide, di-isobutylphenoxyethyl dimethylbenzylammonium chloride, trimethylammonium coconut oil alkyl nitrite, cetylpyridinium fluoride and mixtures thereof.

Illustrative cationic surfactants are quaternary ammonium fluorides described in US Pat. 3,535,421 (to Brinner et al.), Incorporated herein by reference. Some cationic surfactants may also act as germicides in the compositions.

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

In some embodiments of the invention, the synthetic zwitterionic surfactants useful in the present invention can be broadly defined as aliphatic derivatives of quaternary ammonium, phosphonium and sulfonium, i.e. as compounds in which aliphatic radicals can have a branched or unbranched chain, and where one of the aliphatic substituents contains from 8 to 18 carbon atoms, and each of them contains an anionic water-soluble group, for example, carboxy, sulfonate, sulfate, phosphate or phosphonate. Illustrative examples of surfactants that meet the specified requirements for inclusion in the composition include, but are not limited to, sodium alkyl sulfate, sodium lauroyl sarcosinate, cocoamidopropyl betaine and polysorbate 20, as well as 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 0.1 to 5.0%, in another embodiment, from 0.3 to 3.0%, and in another embodiment, from 0.5 to 2.0% of the total weight of the composition.

Flavorants: Oral care compositions of the invention may also include flavorants. Flavorants that are used in the practice of the present invention include, but are not limited to, essential oils, as well as various aromatic aldehydes, esters, alcohols, and the like. Examples of essential oils include peppermint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, marjoram, cinnamon, lemon, lime, grapefruit and orange oils. Chemical compounds such as menthol, carvone and anethole are also useful. Some embodiments of the invention involve the use of peppermint oil and peppermint.

The flavor is included in the composition for caring for the oral cavity in a concentration of from 0.1 to 5% and from 0.5 to 1.5% by weight. The dose of flavor in the individual dosage of the oral composition (i.e., in a single dose) is from 0.001 to 0.05% by weight, and in another embodiment, from 0.005 to 0.015% by weight.

Chelating Agents: The oral care compositions of the invention may also optionally include one or more chelating agents capable of complexing with calcium present in bacterial cell walls. The binding of this calcium weakens the bacterial cell wall and promotes bacterial lysis.

Another group of agents suitable for use as chelating agents in the present invention are soluble pyrophosphates. The pyrophosphate salts used in the present compositions may be any of the alkali metal pyrophosphate salts. In some embodiments, salts include an alkali metal tetrapyrophosphate, a two-alkali metal dihydropyrophosphate, a three-alkali metal monohydropyrophosphate, and mixtures thereof, wherein the alkali metal is sodium or potassium. Salts can be used in their hydrated and unhydrated forms. An effective amount of pyrophosphate salt in the present composition is generally sufficient to provide at least 1.0 by weight of pyrophosphate ions, from 1 to 6%, from 3.5 to 6% by weight of such ions.

Thickeners: When preparing oral care compositions, it is sometimes necessary to add some thickening material to provide the desired consistency or to stabilize or enhance the effect of the drug. In certain embodiments of the invention, the thickeners are carboxyvinyl polymers, carrageenan, hydroxymethyl cellulose, and water soluble salts of cellulose ethers, such as sodium carboxymethyl cellulose and sodium carboxymethyl hydroxyethyl cellulose. Natural resins such as karaya, gum arabic and tragacanth gum can also be used. Colloidal aluminum / magnesium silicate or finely divided silica can be used as a thickener component to further improve the structure of the composition. In some embodiments of the invention, thickeners are used in an amount of from 0.5 to 5.0% by weight, based on 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 proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases, or their compatible mixtures. In some embodiments of the invention, 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. 5000939 (in the name of Dring et al.), U.S. Pat. 4,992,420; U.S. Pat. 4,350,022; U.S. Pat. 4,154,815; U.S. Pat. 4,058,595; U.S. Pat. 3991177; and U.S. Pat. 3696191, all of which are incorporated herein by reference. The enzyme or mixture of several compatible enzymes in the present invention is from 0.002 to 2.0% in one embodiment, or from 0.05 to 1.5% in another embodiment, or in another embodiment, from 0.1 to 0 ,5%.

Water: Water may also be present in the oral compositions of the invention. The water used in the manufacture of commercial oral compositions should be deionized and free of organic impurities. Water typically balances the compositions and comprises from 10 to 90%, from 20 to 60%, or from 10 to 30% by weight of the oral care compositions. This amount of water includes the free water that is added, plus the amount that is added with other materials, for example sorbitol or with any components used in the invention.

Humidifiers: within certain embodiments of the invention, it is also desirable to include a humidifier in the compositions to prevent the composition from drying out when exposed to air. Specific humectants may also give the toothpaste compositions the desired sweet taste or aroma. A moisturizer, based on a clean moisturizer, is generally included in the composition of the toothpaste in an amount of 15 to 70% in one embodiment, or in another embodiment, from 30 to 65% by weight of the composition of the toothpaste. Suitable humectants include edible polyhydric alcohols such as glycerol, sorbitol, xylitol, propylene glycol, as well as other polyols and mixtures of these humectants. Mixtures of glycerol and sorbitol can be used in certain embodiments of the invention as a component of a moisturizer in toothpaste compositions.

In addition to the above components, embodiments of the present invention may include a number of optional components of the toothpaste, some of which are described below. Optional components include, for example, but without limitation, adhesives, foaming agents, flavoring agents, sweeteners, additional anti-plaque agents, abrasives, and coloring agents. These and other optional components are described in detail in US Pat. 5004597 (in the name of Majeti); U.S. Pat. 3,959,458 (to Agricola et al.) And U.S. Pat. 3937807 (in the name of Haefele), all of which are incorporated herein by reference.

Spray drying: suspensions of particles of a substantially insoluble metal, metal salt or metal oxide, for example zinc oxide powder, a surfactant and a coating polymer, are passed through a spray dryer to obtain dried polymer coated microaggregates. Spray drying is a method known in the industry that is useful for preparing free flowing dry powder products from wet starting materials. Spray drying methods are well known in the art. In general, the sizes of the resulting particles depend mainly on the sizes of the particles contained in the feed liquid, and generally vary from 1 to 50 microns, when measured along the main axis, usually ranging from 5 to 30 microns; preferably from 10 to 25 microns in the main dimension. A particularly preferred embodiment of the invention comprises dried polymer coated zinc oxide particles that are generally spherical in shape and have a size of 20 microns in the main dimension.

In addition, as with most materials, the resulting particle sizes vary within the particle size distribution. The resulting particle size distribution is most often single-mode, however, bimodal or polymodal distributions also occur when more than one representative class of sizes is present in the composition of the resulting material. As a rule, the largest number of particles from the sample has a size of more than 5 microns along the main axis or diameter. Preferably, the size range of the microaggregates has a size between about 5 microns and 50 microns.

A person skilled in the art should be familiar with similar methods, and descriptions of useful processes are fully accessible, for example, in US Pat. 6368586, mentioned above, which also provides informative descriptions of alternative ways to obtain highly dispersed free-flowing particles containing metal oxide and polymer, the contents of the specified document is incorporated here by reference, as the full content of the entire document.

EXAMPLE

The preparations according to the mixing procedure were obtained in the proportions indicated in the following table 1.

Table 1 Sample Number one 2 3 four 5 Lot size 120 120 150 120 120 %
(% dry solids) grams %
(% dry solids) grams %
(% dry solids) grams %
(% dry solids) grams %
(% dry solids) grams HPMC
E5 6.33
(17.39) 7.59 9.03
(28.89) 10.84 3.01
(8.28) 4,52 9.03
(24.83) 10.84 3.01
(9.63) 3.61 HPMC
E50 5.71
(15.69) 6.85 3.01
(9.63) 3.61 9.03
(24.83) 13.55 3.01
(8.28) 3.61 9.03 (28.89) 10.84 Zno 18.89
(51.96) 22.67 18.89
(60.46) 22.67 18.89
(51.95) 28.34 18.89
(51.95) 22.67 18.89
(60.46) 22.67 PG 5.12
(14.08) 6.14 0 (0) 0 5.12
(14.08) 7.68 5.12
(14.08) 6.14 0 (0) 0 Tween 80 0.31
(0.85) 0.37 0.31
(0.99) 0.37 0.31
(0.85) 0.46 0.31
(0.85) 0.37 0.31
(0.99) 0.37 Fg-10 0.01
(0.02) 0.01 0.01
(0.03) 0.01 0.01
(0.02) 0.01 0.01
(0.02) 0.01 0.01
(0.03) 0.01 EtOH 5.63 6.75 5.63 6.76 5.63 8.45 5.63 6.76 5.63 6.76 Water 58.01 69.61 58.01 75.74 58.01 87 58.01 69.6 58.01 75.74 Total one hundred one hundred one hundred one hundred one hundred

Additional preparations were obtained using the ingredients listed in table 2.

table 2 Sample Number 8 9 Lot size 120 120 %
(% dry solids) grams %
(% dry solids) grams HPMC E5 12.03
(33.09) 14.44 15.46
(42.52) 18.55 HPMC E50 0
(0) 0 0
(0) 0 Zno 18.89
(51.96) 22.67 15.46
(42.52) 18.56 PG 5.12
(14.08) 6.14 5.12
(14.08) 6.14 Tween 80 0.31
(0.85) 0.37 0.31
(0.85) 0.371 Fg-10 0.01
(0.02) 0.01 0.01
(0.02) 0.0099 EtOH 5.63 6.75 5.63 6.75 Water 58.01 69.61 58.01 69.61 Total one hundred 120 one hundred 120 EtOH / H ₂ O (5.63 / 58) 60 60 Viscosity 430 600 Exit 43% fifty%

The abbreviated names of the ingredients presented in the preceding tables relate to specific ingredients identified as follows: HPMC E5 = hydroxypropyl methyl cellulose E5, HPMC E50 = hydroxypropyl methyl cellulose E50, ZnO = zinc oxide powder, with an average particle diameter of 1 micron, PG = propylene glycol, Tween 80 = surface a polysorbate-based active substance (available from ICI Americas Inc.), FG-10 = anti-foaming agent emulsion (available from Dow Corning), EtOH = ethanol.

Mixing procedure

HPMC E5, HPMC E50, PG and Tween 80 are dissolved in water. Then, ZnO powder is added to the wet components at the same time as ethanol. The materials were mixed until a homogeneous mixture was formed.

Spray Drying Procedure

The resulting wet preparations were introduced into a Buchi B-290 spray dryer with the following parameters: inlet temperature = 170 ° C, outlet temperature = 99-100 ° C, aspiration = 100%, air flow = 40, feed rate = 30% ( 7.2 ml / min).

The material obtained by spray drying was examined using scanning electron microscopy, and it had a bimodal distribution of particles consisting of large spherical ZnO particles coated with a polymer with a diameter of approximately 20 μm and particles of an irregular shape of the dried polymer, with a size of approximately 5 μm in the main measurement.

Small amounts of samples 1-6 of the material obtained by spray drying were placed on glass plates. 50 μl of a glycerol / water mixture (1: 4) was added to each plate. The viscosity of the glycerol / water mixture was 1.76 cPz (mPa⋅s). Particles were monitored under a microscope (4x magnification). The time during which the sample disintegrated in the fastest manner was recorded, as well as the time when the level of sample disintegration was 50%, 75%, 90%, and 99%. The time values are presented in Table 3.

Table 3 Sample Number Attitude
E5 / E50 Maximum dissolution rate 50% dissolution 75% dissolution 90% dissolution 99% dissolution minutes one 1,11 1,5 3 5 eleven 2 1,11 1.83 3 4,5 6.5 eleven 3 0.33 1,58 2.83 5 12 thirty four 3 one 1.33 2.5 5 6.33 5 3 1.25 2 3.25 5 6 6 0.33 1,67 3.33 6.5 fifteen 24

Absorption method

VITRO-SKIN® is a substrate that effectively mimics the surface properties of human skin. It contains optimized protein and lipid components, and has a topography, pH value, critical surface tension and ionic strength identical to those of human skin. VITRO-SKIN was cut into square plates corresponding to the size of the NAP discs (12.4 × 12.4 mm = ½ × ½ inches). Samples were rinsed with hexane three times and then incubated overnight with 1 ml of saliva at 37 ° C (each measurement was performed in triplicate). Two suspension samples were prepared in deionized water containing 1% ZnO suspension, spray dried and a 0.5% ZnO powder suspension, respectively. The saliva from the tubes that contained VITRO-SKIN was aspirated. To each tube was added 2 ml of a suspension of ZnO. From the tubes, the suspension was aspirated and rinsed with 5 ml of water (rotation in 1 × 10 sec). The tubes were again rinsed with 5 ml of water (rotation in 1 × 10 sec). VITRO-SKIN samples were transferred to new tubes and rinsed with 1 ml of HCl (1M) with rotation for 30 seconds. Then added 4 ml of DI water and left alone for 2 hours, with periodic rotation. The solution was then analyzed by atomic spectrometry in order to measure the concentration of zinc. The amounts of ZnO absorbed by the samples were measured on a μg / plate basis, and the results are shown in Table 4.

Table 4 Sample Number The amount of ZnO based on one plate,
mcg Average value Standard deviation 1 (ZnO powder) 122,4795 107.7 13.8 2 (ZnO powder) 95.15808 3 (ZnO powder) 105,4269 1 (ZnO, spray drying) 183.5947 181.4 18.6 2 (ZnO, spray drying) 161.8123 3 (ZnO, spray drying) 198.8424

The absorption of ZnO on VITRO-SKIN is a simplified liquid toothpaste model. Spray-dried ZnO powder was surprisingly more effective in absorbing ZnO on VITRO-SKIN.

In vitro efficacy test

The effectiveness of the samples was tested and evaluated by inhibition of zonal microbial growth. Spray-dried ZnO worked better than untreated ZnO powder.

Claims (14)

1. An antimicrobial microaggregate comprising a zinc oxide particle stabilized with a nonionic surfactant and coated with a polymer, wherein the polymer is hydroxypropyl methylcellulose and where the average microaggregate size is from 5 microns to 50 microns in the main size. 2. The microaggregate according to claim 1, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene sorbitan and fatty acid ether, polyoxyethylene sorbitan ether and fatty alcohol, polyhydroxyethylene ether and monocarboxylic fatty acid, polyhydroxyethylene ether and dicarboxylic fatty acid ether or simple and fatty alcohol. 3. The microaggregate according to claim 2, wherein the surfactant comprises polysorbate 80. 4. The microaggregate according to claim 1, wherein the microaggregate is formed by spray drying a mixture comprising zinc oxide particles, a surfactant, and a water soluble polymer. 5. The micro-aggregate according to any one of paragraphs. 1-4, where the microaggregator comprising the polymer coated zinc oxide particle is predominantly spherical in shape and has an average size of 20 microns in the main size. 6. The composition for the care of the oral cavity, including many microaggregates according to any one of paragraphs. 1-5. 7. The composition of claim 6, wherein the composition is a toothpaste. 8. A method of delaying the accumulation of plaque and / or tartar, comprising contacting the surfaces of the oral cavity with a composition according to any one of paragraphs. 6 or 7. 9. A method of obtaining a variety of microaggregates according to any one of paragraphs. 1-5, including: mixing the coating polymer, which is hydroxypropyl methylcellulose, zinc oxide, and a surfactant in a suitable solvent or carrier, spray drying the mixture and the allocation of thus obtained microaggregates, where the average size of the microaggregates is from 5 microns to 50 microns in the main size. 10. The method of claim 9, wherein the hydroxypropyl methylcellulose, zinc oxide, and surfactant are further mixed with a non-polymer carrier and / or anti-foaming agent. 11. The composition according to any one of paragraphs. 6 and 7 for use to slow the accumulation of plaque and / or tartar.