CA2711263A1 - Compositions and methods for the treatment of xerostomia - Google Patents
Compositions and methods for the treatment of xerostomia Download PDFInfo
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- CA2711263A1 CA2711263A1 CA2711263A CA2711263A CA2711263A1 CA 2711263 A1 CA2711263 A1 CA 2711263A1 CA 2711263 A CA2711263 A CA 2711263A CA 2711263 A CA2711263 A CA 2711263A CA 2711263 A1 CA2711263 A1 CA 2711263A1
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- basic amino
- amino acid
- ion source
- arginine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
- A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The present invention is directed to methods and compositions comprising a basic amino acid, e.g., arginine, for the treatment of dry mouth.
Description
COMPOSITIONS AND METHODS FOR THE TREATMENT OF
XEROSTO IA
100011 This application claims the benefit of t nited States Patent Application Serial No.
61/027,438 filed February 9, 2008. and also claims the benefit of United States Patent Application Serial No. 61%027.442 filed February 9, 2008, and United States Patent Application Serial Nos. 61/027,432:61/027,431:61/027,420; and 61/027,135 all filed February 8, 2008, the contents of which applications are all incorporated herein by reference.
BACKGROUND OF THE INVENTION
100021 Dry mouth or xerostomia is an acute or chronic condition primarily caused by the lack of saliva. It may he caused by an underlying disease, such as Sj6gren's syndrome, dehydration, trauma to the salivary glands, consumption of alcohol, or a side effect to medications. It has been identified as a condition increasing in the general population.
Roughly 15% to 20% of young adults complain of oral dryness, and 30 -- 40% of people ages 60 - 80 complain of oral dryness.
100031 Xerostomia may cause several complications in patients. Saliva may be decreased, and may be foamy, thick and ropy. The tongue may be dry, fissured, lohtilated, and may be infected with various bacteria and yeasts. Cheeks are often dry, dull and pale. The decreased moisture in the mouth creates difficulties in eating, as the chewing and swallowing of food is exacerbated by the lack of saliva. This also interferes with a person"s ability to taste food, and produce speech. Furthermore, a moist mouth is beneficial in intimate human relations, which may also suffer as a result of dry mouth, 100041 Patients suffering from xerostotnia also suffer from extensive dental decay., e.g., caries, including areas not usually prone to decay. such as the lower incisors and roots. One possible explanation is that pellicle. which is present in saliva, provides a protective barrier between acids and a tooth surface, and such a barrier is reduced in the absence of saliva.
100051 There are numerous products available to alleviate dry mouth, including oral moisturizing rinses. gels and synthetic saliva sprays, but there are few products y':Ili, h provide an anticaries effect. Current oral products for the trcatment of dry'-mouth require t n ?tions of t1LPC3 ido "? lower their risk caries.
:,!!(?(i z eontin I~^ I oral ca dry i i . . Tlx re is also a continuing need to d , slop oral care c . 1 IIav 1.
aid in the consumption of foods, and production of speech in persons suffering from dry mouth.
SUMMARY OF THE INVENTION
100071 The use of basic amino acids. e.g., arginine, in toothpaste formulations is known in the art. however, the inventors have discovered an unexpected and surprising result when toothpastes comprising arginine bicarbonate are used by persons suffering from xerostoÃnia, that is, such compositions alleviate, treat, and inhibit dry mouth. It is believed that basic amino acids, e.g., arginine may be used to prevent cavities without or without fluoride, as basic amino acid salts, e.g., argi nine-bi carbonate, in combination with an insoluble calcium salt, typically the dentifrice abrasive mimics the protective effects of saliva against caries and provides complete protection of the tooth enamel and roots by coating the tooth.
100081 The invention thus comprises Composition 1.0, an oral care composition for the treatment, prevention, amelioration, or inhibition of dry mouth comprising an effective amount of a basic amino acid., e.g., arginine, in free or salt form, e.g., present in an amount of at least I % (by weight of free base) where the formulation is a dentifrice or 0.1 % where the formulation is a mouth rinse; the formulation optionally further comprising one or more of i. a calcium and/or phosphate ion source, e.g., calcium carbonate and/or a soluble calcium salt, e.g., calcium chloride, calcium lactate;
ii, a soluble phosphate salt, e.g., potassium. phosphate monobasic or dibasic potassium phosphate; andsor iii. a calcium phosphate, e.g.. dicalcium phosphate; a potassium ion source, e.g., potassium chloride, potassium phosphate monohasic or dibasic potassium phosphate, and/or potassium nitrate;
iv. a fluoride source. e.g., a soluble fluoride salt. e,g., sodium fluoride or sodium monoiluorophosphate:
v, a magnesium source, e.g., magnesium chloride; a flavorant which induces saliva flow, e.g., capsacien.; and/'or vi. polyol hume ',fit"??, ;. elected from s; vecrol. sugar alcohols (e.g ST~e 1Ø1. Composition 1.0 the basic ainii , orr.. diaminobutanoic acic`, C W in ~~ii%
1Ø2. Composition 1.0 or 1Ø1 wherein the basic amino acid has the L-configuration.
1Ø3. Any of the preceding compositions is provided in the form of a salt of a di- or tri-peptide comprising the basic amino acid.
1Ø4. Any of the preceding compositions wherein the basic amino acid is arginine.
1Ø5. Any of the preceding compositions wherein the basic amino acid is L-arginine.
1Ø6. Any of the preceding compositions wherein the basic amino acid is partially or wholly= in salt form.
1Ø7. Composition 1Ø6 wherein the basic amino acid is arginine phosphate.
1Ø8. Composition 1Ø6 wherein the basic amino acid is in the form of arginine hydrochloride.
1Ø9. Composition 1Ø6 wherein the basic amino acid is arginine sulfate.
1Ø10. Composition 1Ø6 wherein the basic amino acid is arginine bicarbonate.
1Ø1.1. Any of the preceding compositions wherein a salt of the basic amino acid is formed in situ in the formulation by neutralization of the basic amino acid with an acid or a salt of an acid.
1Ø12. Any of the preceding compositions wherein the salt of the basic amino acid is formed by neutralization of the basic amino acid to form a premix prior to combination with the fluoride salt.
1Ø13. Any of the preceding compositions wherein the basic amino acid is present in an amount corresponding to about 0.1 --- 20%, e.g., about 1 wt. % to about 10 wt.
% of the total composition weight, the weight of the basic amino acid being calculated as free base form.
1.Ø14. Composition 1.Ø1 1. wherein the basic amino acid is present in an amount of about 7.5 wt. I ofthe total composition fight.
1..03.15. Cor1Ø1 ar i.: acid is present in an amour f 1Ø16. C._>r ro acid 3.75 wt. %
1Ø17. Compositi= 1Ø1 1 to iv O rcid In an amount of about l.. 5 wt. % of th 1Ø15. Any of the preceding compositions wherein the fluoride salt is stannous fluoride, sodiurrt fluoride, potassium fluoride. sodium monofluorophosphate_ sodium fluorosilicate, : '-octadec v ltrimethvlend ia nine i ;ti,NN'-ammonium Ouorosilicate, amine fluoride (e.g..
tris(2-ethanot)-dihydrotluoride'). amr oniurn fluoride, titanium fluoride, hexaf u.orosulfate, and combinations thereof.
1Ø19. Any of the preceding compositions wherein the fluoride salt is a fluorophosphate.
1Ø20. Any of the preceding composition wherein the fluoride salt is sodium monofluorophosphate.
1Ø21. Any of the preceding compositions where the fluoride salt is sodium fluoride.
1Ø21 Any of the preceding compositions wherein the fluoride salt is present in an amount of about 0.01 wt. % o to about 2 wt. % of the total composition weight.
1.023. Any of the preceding compositions wherein the fluoride salt provides fluoride ion in an amount of about 0.1. to about 0.2 wt. % of the total composition weight.
1Ø24. Any of the preceding compositions wherein the soluble fluoride salt provides fluoride ion in an amount of from about 50 to 10,000 ppm.
1Ø25. Any of the preceding compositions which is a mouthwash having 100 to about 250 ppm available fluoride ion.
1Ø26. Any of the preceding compositions which is a dentifrice having about 750 to 2000 ppm available fluoride ion.
1Ø2-7. Any of the preceding compositions wherein the composition comprises 750 to 2000 ppm fluoride ion.
1.Ø25. Any of the preceding compositions wherein the composition comprises .000 to 1500 ppm fluoride ion.
1Ø29. Any ofthe preceding compositions wherein the composition comprises about 1450 ppm fluoride ion.
_030_ Any ;t the. pH is r=
9. e.
Ø3 g . An oft! ie P1po . `s t w pH is _ ')out ,.. tt 7.4.
1Ø32. Any of he preceding compositions wherein the pH is --- n ab- a ,.J
about 1Ø33. Any of the preceding compositions wherein the pH is approximately neutral.
1Ø34. Any of the preceding compositions further comprising an abrasive or particulate.
1Ø35, The immediately preceding composition wherein the adhesive or particulate is selected from sodium bicarbonate, calcium phosphate (e.g., dicalcium phosphate dihydrate), calcium sulfate, precipitated calcium carbonate, silica (e.g..
hydrated silica), iron oxide, aluminum oxide, perlite, plastic particles, e.g., polyethylene, and combinations thereof.
1,0.36. The immediately preceding composition wherein the abrasive or particulate is selected from a calcium phosphate (e.g., dicalcium phosphate dihydrate).
calcium sulfate, precipitated calcium carbonate, silica (e.g., hydrated silica), and combinations thereof.
1.037. Any of the preceding compositions comprising an abrasive in an amount of about 15 wt. % to about 70 wt. % of the total composition weight.
1Ø38. Any of the preceding compositions comprising a small particle abrasive fraction of at least 5% having a d50 of <5 micrometers.
1Ø39. Any of the preceding compositions having a RDA of less than 150, e.g., about 40-140.
1Ø40. Any of the preceding compositions wherein the anionic surfactant is selected from a. water-soluble salts of higher fatty acid monoglyceride monosulfates (e.g., the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids such as sodium N-methyl N-cocoyl taurate, sodium cocomo-glyceride sulfate), h. higher alkyl sulfates, e.g., sodium lauryl sulfate, c. higher alkyl-ether sulfates, e.g., of formula CH.~(CfH-;mCf1-(OCfI-Cf ~),OSO5 ., wherein in is 6-16, e.g:., .10, n is 1-6, e.g., 2, d urn ianreth-2 sodi.n ~.~ , 0.,:: _..w `h as sodium laurvi ~jurii ( ~j t~E ~.~~1 v. htt 3` [[ F~~ ~=~~~ 1 ";- =i:- ie5.+ I `'-1 I
sulfeacetate), higher fatty acid esters of 1,2 dihydroxy propane sulfonate, sulfocolaurate (N-2-ethyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate), f. and mixtures thereof By "higher alkyl" is meant, e.g., G--'0 alkyl, In particular embodiments. the anionic surfactant is selected from sodium lauryl sulfate and sodium ether lauryl sulfate.
1Ø41. Any of the preceding compositions wherein the anionic surfactant is selected from sodium lauryl sulfate, sodium ether lauryl sulfate, and mixtures thereof.
1Ø42. Any of the preceding compositions wherein the anionic surfactant is present in an amount of from about 0.3% o to about 4.5% by weight.
1Ø43. Any of the preceding compositions additionally comprising surfactants selected from cationic, zwitterionic, and nonionic surfactants, and mixtures thereof.
1Ø44. Any of the preceding compositions comprising at least one humectant.
1Ø45. Any of the preceding compositions comprising at least one humectant selected from glycerin, sorbitol and combinations thereof.
1Ø46. Any of the preceding compositions comprising xylitol.
1Ø47. Any of the preceding compositions comprising at least one polymer.
1Ø4$. Any of the preceding compositions comprising at least one polymer selected from polyethylene glycols, polyvinyimethyl ether malefic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum), and combinations thereof.
1Ø49. Any of the preceding compositions comprising gum strips or fragments.
1Ø50. Any of the preceding compositions comprising f lavorinsg, fragrance andi.or coloring.
1Ø51, Any. of the preceding scions, %
1Ø52. ... l .. .. i._~ tip .- 1 i r -V e carvac.'oi, citral, hinoi.. tol, catechol, n ley 1 e._ `ar4 ~,. __il n = :3i1 to , e pi `ecl in, gallic acid, mis yak extract, sea-buckthorn c r;a ?. bisguanide antiseptics chlorhexidine. alexidine or octenidine'), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecy 1-4-ethy lpy rid ini um chloride (TD ~OL) i~
phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salilluor, metal ions (e.g.- zinc salts, for example, zinc citrate, stannous salts, copper salts, iron salts). sanguinarine, propolis and oxygenating agents (e.g.. hydrogen peroxide, buffered sodium peroxy borate or peroxycarbonate), phthalic acid and its salts, monoperthalic acid and its salts and. esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol.
octapinol and other piperidino derivatives, nicin preparations, chlorite salts; and mixtures of any of the foregoing.
1Ø53. Any of the preceding compositions comprising an anti-inflammatory compound, e.g., an inhibitor of at least one of host pro-inflammatory factors selected from matrix metal loprotei nases (MMP's), cyclooxytgenases (COX), PG17, interleukin 1 (IL-1), II--1(l converting enzyme (ICE), transforming growth factor I (TGF-3I). inducible nitric oxide synthase (iNYOS). hyaluronidase, cathepsins, nuclear factor kappa B (NF- B), and IL-I
Receptor Associated Kinase (IRAK), eg, selected from aspirin. ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, aspirin, ketoprofen, piroxicam, meclofenamIc acid, nordihydoguaiarctic acid, and mixtures thereof 1Ø54. Any of the preceding compositions comprising an antioxidant, e.g., selected from the group consisting of Co-enzyme Q10, PQQ. Vitamin C, Vitamin E, Vitamin A.
anethole-dithiothione, and mixtures thereof.
1Ø55. Any of the preceding compositions wherein the anti-microbial is poorly soluble.
1Ø56. Any of the preceding compositions comprising triclosan.
1Ø57. Any of the preceding compositions comprising triclosan and xylitol.
1Ø58. Any of the preceding compositions comprising triclosan, xylitot, and precipitated calcium carbonate.
p antib c 1Ø59. Any of of 0.01 - 5 wt. ie , ._.r 1p - i' i- weight.
1Ø60. Any of the i ccding compositions comprising triclosan in an aTf oui:.
wt. percent (e tfl i )-:i`IC7~ t.
0.3% of the total composition weight.
1Ø62. Any of the preceding compositions comprising a whitening agent.
1Ø63. Any of the preceding compositions comprising a whitening agent selected from a whitening active selected from the group consisting of peroxides. metal ch[orites, perborates, percarbonates. peroxyacids, hy=poch.lorites, and combinations thereof 1Ø64. Any of the preceding compositions comprising hydrogen peroxide or a hydrogen peroxide source, e.g., urea peroxide or a peroxide salt or complex (e.g., such as peroxyphosphate. peroxycarbonate, perborate. peroxysilicate, or persulphate salts, for example calcium peroxyphosphate. sodium perborate, sodium carbonate peroxide, sodium peroxvphosphate. and potassium persulfate).
1Ø65. Any of the preceding compositions further comprising an agent that interferes with or prevents bacteria] attachment, e.g., solbrol or chitosan.
1Ø66. Any of the preceding compositions further comprising a source of calcium and phosphate selected from (i) calcium-glass complexes, e.g., calcium sodium phosphosilicates, and (ii) calcium-protein complexes, e.g., casein phosphopeptide-amorphous calcium phosphate.
1Ø67. Any of the preceding compositions further comprising a soluble calcium salt. e.g., selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.
1Ø68. Any of the preceding compositions further comprising a physiologically acceptable potassium salt, e.g., potassium nitrate or potassium chloride, in an amount ef'lective to reduce dentinal sensitivity.
1Ø69. Any of the preceding compositions comprising from about 0.1 % to about 7.5 o of a physiologically acceptable potassium salt, e.g., potassium nitrate and./or potassium chloride.
1 .C.70. DA of the nr .: d oan Rio, which i a . .,,1 cr.>rtpr. :
iÃ
--.0111c Sur ..t .,.t. 1'- .
monofluorn or soy iumti fiu e j j).71. Any of tf,~ preceding con ti tt 3 ") ;li L: th oral cal itti.
e,-- with brushing, to reduce dry,' m; o 11 ~j 11 _~ M r ion cif hydrating effects. and optionally to (i) reduce or inhibit formation of dental caries.
e.g., caries which result from reduced saliva flow and dry mouth, (ii) reduce, repair or inhibit early enamel lesions, e.g.. as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), (iii) reduce or inhibit demineralization and.
promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial hiof lm formation in the oral cavity, (x) raise and~'or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xiii) enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, and/or (xiv) reduce erosion of the teeth, (xv) whiten the teeth. (xvi) immunize the teeth against cariogenic bacteria. (xvii) clean the teeth and oral cavity, and (xviii) reduce steep disruption due to dry mouth.
1Ø72. A composition obtained or obtainable by combining the ingredients as set forth in any of the preceding compositions.
1Ø73. Any ofthe preceding compositions in a form selected from snouthrinse, toothpaste, tooth get, tooth powder, non-abrasive gel, mousse, foam, mouth spray, lozenge, oral tablet, dental implement, and pet care product.
1Ø74. Any of the preceding compositions wherein the composition is toothpaste.
1Ø75. Any of the preceding compositions wherein the composition is a toothpaste optionally further comprising one or more of one or more of water, abrasives, surfactants, foaming agents. vitamins, polymers, enzymes, humectantas, thickeners, antimicrobial agents, preservatives, flavorings. colorings and/or combinations thereof.
1Ø76. Any of the preceding compositions 1.0 - 1Ø72 wherein the composition is a mouthwash.
1Ø77. Any of the preceding compositions 1.0 - 1Ø72 wherein the composition is a the-i 10.7. r . -,i (00091 Levels of active ingredients will vary based on the nature of the deliver.
the particular active. For example. the basic amino acid may be present at levels fro:`., rr o about 0.1 to about 20 wt %(expressed as weight of free base), e.g., about 0.1 to about 3 wt %
for a mouthriuse, about I to about 10 wt % for a consumer toothpaste or about 7 to about 20 wt % for a professional or prescription treatment product. Fluoride may be present at levels of, e.g,, about 25 to about 25.000 ppm, for example about 25 to about 250 ppm for a mouthrinse, about 750 to about 2,000 ppm for a consumer toothpaste, or about 2,000 to about 25.000 ppm for a professional or prescription treatment product. Levels of antibacterial will vary similarly. with levels used in toothpaste being e.g., about 5 to about 15 times greater than used in mouthrinse. For example, a triclosan mouthrinse may contain, e.g., about 0.03 wt % triclosan while a triclosan toothpaste may contain about 0.3 wt %
triclosan.
100101 The present invention also includes Method 2Ø a method for treating, inhibiting or relieving dry- mouth comprising introducing into the oral cavity to a patient in need thereof, e.g., suffering from dry mouth, an oral care composition comprising a basic amino acid in free or salt form, e.g., any one of compositions 1.0 ---- 1Ø78.
100111 Additional embodiments of the present invention also include the following methods:
2.1 Of method 2Ø wherein the method is also effective (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit early enamel lesions. e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (fCM), (iii) reduce or inhibit demineralization and promote remineralization of the teeth.
(iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial biofilm formation in the oral cavity, (x) raise and/or maintain plaque pl-I at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xiii) enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, and/or (xiv) reduce erosion of the teeth, and/or (xv) clean the teeth and oral cavity.
2.2 Of methods 2.0 or 2.2 wherein the composition comprises at least 7.5%
argini.ne.
2.3 Of methods 2.0 --- 2.2 wherein the composition comprises at least 1.0%
arginine bicarbonate.
2. 2,0 ofa hurnectaut, 2.5 O .:, 2,4 2, Of'r. _ t+-:3 2.0 2.whc'f 2.7 Of met hods 2.0 - 2.6 wherein the pe~tient l ~ L.1I rood stuff as a result ofdrv mouth.
2.g Of methods 2.0 -2.7 wherein the patient has difficulty swallowing as a result ofdry mouth.
2.9 Of methods 2.0 - 2.8 wherein the patient has speech difficulties as a result of dry mouth.
2.10 Of methods 2.0 --2,9 wherein the patient also suffers from opportunistic infection of the tongue as a result of dry mouth.
2.11 Of methods 2.0 - 2.10 wherein. dry mouth is caused by a disease.
2.12 Of methods 2.0 -2. 11 wherein the patient is being treated with a medicament, said medicament causing said dry mouth.
2.13 Of methods 2.0 - 2.12 wherein dry mouth is chronic.
2.14 Of methods 2.0 - 2.13 wherein the composition comprises from about 7r.5 o to about 25.0 % arginine.
2.15 Of methods 2.0 - 2,14 wherein the composition is a dentifrice.
2.16 Of methods 2.0 --- 2.15 wherein the composition is a toothpaste.
2.1.7 Of methods 2.0 - 2.16 wherein the composition is a gel.
2.18 Of methods 2.0 - 2.17 wherein the composition is applied in the oral cavity with a tooth brush.
2.19 Of methods 2.0 -- 2.15 wherein the composition is a mouth wash.
2.20 Of methods 2.0 - 2.19 wherein the patient performs the method more than once a day.
2.21 Of methods 2.0 -- 2.20 wherein the patient performs the method daily.
100121 The present invention also contemplates the use of a basic amino acid in free or salt form, e.g., arginine, e.g., as provided in any of compositions 1.0 -1Ø75, for the treatment, amelioration, inhibition, and/or prevention. of dry mouth.
100131 The present invention further provides the use of a basic amino acid, in free or salt form, for the manufacture of a medicament for treating, ameliorating, inhibiting or preventing drys mouth.
t t3 t t [_, 1 -rov?des bdsc d, in free or szf a -- tfi.
y 100151 it r_, ~; ;tad ctm r prevention, era iu; m11 nt, I.inhihitic o ':.ef'. tomnia in a patient suffering ti' :relroa . In one embodiment, the patient. suffers from, or is predisposed to xerostomia h"
sir injury. In another embodiment, the patient suffers from, or is predisposed to xerostomia by treatmmnent(s) of medicaments which cause xerostomia. wherein the dry mouth is a side effect of the medicament.
100161 The term "treat" or "ameliorate" is used herein to mean that administration of a composition of the present invention mitigates a condition in the patient, preferably a mammal, more preferably, a human.
(00171 The term "inhibit" is used herein to mean that administration of a composition of the present invention delays the onset of a condition, e.g., by 6 hours, 12 hours. 24 hours, 48 hours, or 96 hours following the administration of the composition.
[00181 The term "prevent" does not imply that a particular condition will be completely avoided in the future, rather, that the particular condition will be avoided until the patient is able to administer the compositions of the present invention at a second time point, e.g., within 12 hours, 24 hours, 48 hours, or 96 hours of an initial administration.
100191 Without intending to be fund by a particular theory, it is hypothesized that a significant factor in the beneficial effect of arginine is that arginine may be metabolized by certain types of bacteria, e.g., S. sanguis which are not cariogenic and which compete with cariogenic bacteria such as S. mulans, for position on the teeth and in the oral cavity. The arginolytic bacteria can use arginine and other basic amino acids to produce ammonia, thereby raising the p1l of their environment, while cariogenic bacteria metabolize sugar to produce lactic acid, which tends to lower the plaque pl-I and demineralize the teeth, ultimately leading to cavities. It is believed that regular use of a Composition of the Invention, over time, will lead to a relative increase in the arginolytic bacteria and a relative decrease in the cariogenic bacteria, resulting in a higher plaque pl-I
(notwithstanding that the Composition of the Invention is itself generally pH neutral, the basic amino acid having been neutralized by an inorganic oxoacid). It is believed. that this pH-raising effect may be accomplished in compositions which are substantially free of fluoride. It is also believed that this pff-raising effect may be mechanistically separate from and complementary to the effect of fluoride in promoting remineralization and strengthening the to.--,.h enamel.
[00201 Conce i _ r. t t -re c{,. , 'r nr _ ZL MY be õ
Z;A b,_7 ind by then is Y ;Igher le~~ i ~'_ 1 I
7.50%. that is, from about r.5 to about 5 =fl, from about 8 about 20%. from e -t, i 9% to about 15%, or about 10% coat teeth, gums, and/or the oral cavity, leaving a perception that the mouth has been moisturized or hydrated.
100211 Compositions of the present invention may be in the form of a dentifrice comprising additional ingredients selected from one or more of'water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humeetants, thickeners, antimicrobial agents. preservatives, flavorings, colorings and/or combinations thereof.
100221 The basic amino acids which can be used in the compositions and methods of the invention include not only naturally occurring basic amino acids, such as arginine, lysine, and histidine, but also any basic amino acids having a carboxyl group and an amino group in the molecule, which are water-soluble and provide an aqueous solution with a pli of 7 or greater. Accordingly, basic amino acids include, but are not limited to, arginine, lysine, citrullene, ornithine, creative, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In a particular embodiment, the basic amino acids are selected from arginine, citrullene, and ornithine. In certain embodiments, the basic amino acid is arginine, for example, L,-arginine, or a salt thereof.
100231 The compositions of the invention are intended for topical use in the mouth and so salts for use in the present invention should be safe for such use, in the amounts and concentrations provided. Suitable salts include salts known in the art to be pharmaceutically acceptable salts are generally considered to be physiologically acceptable in the amounts and concentrations provided. Physiologically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic acids or bases, for example acid addition salts formed by acids which form a physiological acceptable anion, e.g., hydrochloride or bromide salt, and base addition salts formed by bases which form a physiologically acceptable cation, for example those derived from alkali metals such as potassium and sodium or alkaline earth metals such as calcium and magnesium.
Physiologically acceptable salts may be obtained using standard procedures known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically, acceptable anion.
~ a sic amino acid present in an amount of about 7,5 ~002~f Ire various ~:nibc~e_ `:.-. i-s, 1 % ~3,ttc w i_ '.a Wit. , F, A e about 1. 5wt. or ". 5 wt.
of 100251 The oral care may further include one or more fluoride on sources, e. ,., soluble fluoride salts. A wide variety of fluoride ion-vieldin.g materials can be employed as sources of soluble fluoride in the present compositions, and such materials are known to those of skill in the art, Examples of suitable fluoride ion-yielding materials are found in U.S. Pat. No. 3,535,421, to Briner et al.; U.S. Pat, No. 4,885.155.
to Parran, Jr. et a.. and U.S. Pat.' o. 3.678,154, to Widder et al., incorporated herein by reference.
100261 Representative fluoride ion sources include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate. ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In certain embodiments the fluoride ion source includes stannous fluoride, sodium fluoride, sodium monofluorophosphate as well as mixtures thereof.
100271 In certain embodiments, the oral care composition of the invention may also contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 25 ppm to 25,000 ppm of fluoride ions, generally at least about 500 ppm, e.g., about 500 to about 2000 ppm, e.g.. about 1000 to about 1600 ppm, e.g., about 1450 ppm.
The appropriate level of fluoride will depend on the particular application. A
mouthwash, for example, would typically have about 100 to about 250 ppm fluoride. A
toothpaste for general consumer use would typically have about 1.000 to about 1.500 ppm, with pediatric toothpaste having somewhat less. A dentifrice or coating for professional application could have as much as 5,000 or even 25,000 ppm fluoride.
100281 In certain embodiments, the oral care composition of the invention may contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 100 ppm to 10,000 ppm of fluoride ions, e.g., 1000-2000 ppm..
100291 The Compositions of the Invention may comprise a calcium phosphate abrasive, e.g., tricalcium phosphate (Ca-,(1'O)) ), hydroxyapatite (Ca, (PO4)6(OH)2), or dicalcium phosphate dihydrate (CaFIP04 ; = 2H_O. also sometimes referred to herein as DiCal) or calcium pyrophosphate.
100301 The compositions may include one or more additional abrasives known by those of skill in the art, for example silica abrasives such as precip tatccd silicas having a mean particle size of up to about 20 microns, such as Icodent I 1 marketed by J. M.
Iluber.
==i , . m'.~ipl3Lls~,l __C;. lil Sp hate.
;r t ~reraii have n avera e pa tici,~ iz ut 30 micron.
about between 5 and about 15 microns. The silica s,~3rasiv'es can be from precipitated silica or silica gels, such as the silica xerogels described in U.S. Pat. No.
XEROSTO IA
100011 This application claims the benefit of t nited States Patent Application Serial No.
61/027,438 filed February 9, 2008. and also claims the benefit of United States Patent Application Serial No. 61%027.442 filed February 9, 2008, and United States Patent Application Serial Nos. 61/027,432:61/027,431:61/027,420; and 61/027,135 all filed February 8, 2008, the contents of which applications are all incorporated herein by reference.
BACKGROUND OF THE INVENTION
100021 Dry mouth or xerostomia is an acute or chronic condition primarily caused by the lack of saliva. It may he caused by an underlying disease, such as Sj6gren's syndrome, dehydration, trauma to the salivary glands, consumption of alcohol, or a side effect to medications. It has been identified as a condition increasing in the general population.
Roughly 15% to 20% of young adults complain of oral dryness, and 30 -- 40% of people ages 60 - 80 complain of oral dryness.
100031 Xerostomia may cause several complications in patients. Saliva may be decreased, and may be foamy, thick and ropy. The tongue may be dry, fissured, lohtilated, and may be infected with various bacteria and yeasts. Cheeks are often dry, dull and pale. The decreased moisture in the mouth creates difficulties in eating, as the chewing and swallowing of food is exacerbated by the lack of saliva. This also interferes with a person"s ability to taste food, and produce speech. Furthermore, a moist mouth is beneficial in intimate human relations, which may also suffer as a result of dry mouth, 100041 Patients suffering from xerostotnia also suffer from extensive dental decay., e.g., caries, including areas not usually prone to decay. such as the lower incisors and roots. One possible explanation is that pellicle. which is present in saliva, provides a protective barrier between acids and a tooth surface, and such a barrier is reduced in the absence of saliva.
100051 There are numerous products available to alleviate dry mouth, including oral moisturizing rinses. gels and synthetic saliva sprays, but there are few products y':Ili, h provide an anticaries effect. Current oral products for the trcatment of dry'-mouth require t n ?tions of t1LPC3 ido "? lower their risk caries.
:,!!(?(i z eontin I~^ I oral ca dry i i . . Tlx re is also a continuing need to d , slop oral care c . 1 IIav 1.
aid in the consumption of foods, and production of speech in persons suffering from dry mouth.
SUMMARY OF THE INVENTION
100071 The use of basic amino acids. e.g., arginine, in toothpaste formulations is known in the art. however, the inventors have discovered an unexpected and surprising result when toothpastes comprising arginine bicarbonate are used by persons suffering from xerostoÃnia, that is, such compositions alleviate, treat, and inhibit dry mouth. It is believed that basic amino acids, e.g., arginine may be used to prevent cavities without or without fluoride, as basic amino acid salts, e.g., argi nine-bi carbonate, in combination with an insoluble calcium salt, typically the dentifrice abrasive mimics the protective effects of saliva against caries and provides complete protection of the tooth enamel and roots by coating the tooth.
100081 The invention thus comprises Composition 1.0, an oral care composition for the treatment, prevention, amelioration, or inhibition of dry mouth comprising an effective amount of a basic amino acid., e.g., arginine, in free or salt form, e.g., present in an amount of at least I % (by weight of free base) where the formulation is a dentifrice or 0.1 % where the formulation is a mouth rinse; the formulation optionally further comprising one or more of i. a calcium and/or phosphate ion source, e.g., calcium carbonate and/or a soluble calcium salt, e.g., calcium chloride, calcium lactate;
ii, a soluble phosphate salt, e.g., potassium. phosphate monobasic or dibasic potassium phosphate; andsor iii. a calcium phosphate, e.g.. dicalcium phosphate; a potassium ion source, e.g., potassium chloride, potassium phosphate monohasic or dibasic potassium phosphate, and/or potassium nitrate;
iv. a fluoride source. e.g., a soluble fluoride salt. e,g., sodium fluoride or sodium monoiluorophosphate:
v, a magnesium source, e.g., magnesium chloride; a flavorant which induces saliva flow, e.g., capsacien.; and/'or vi. polyol hume ',fit"??, ;. elected from s; vecrol. sugar alcohols (e.g ST~e 1Ø1. Composition 1.0 the basic ainii , orr.. diaminobutanoic acic`, C W in ~~ii%
1Ø2. Composition 1.0 or 1Ø1 wherein the basic amino acid has the L-configuration.
1Ø3. Any of the preceding compositions is provided in the form of a salt of a di- or tri-peptide comprising the basic amino acid.
1Ø4. Any of the preceding compositions wherein the basic amino acid is arginine.
1Ø5. Any of the preceding compositions wherein the basic amino acid is L-arginine.
1Ø6. Any of the preceding compositions wherein the basic amino acid is partially or wholly= in salt form.
1Ø7. Composition 1Ø6 wherein the basic amino acid is arginine phosphate.
1Ø8. Composition 1Ø6 wherein the basic amino acid is in the form of arginine hydrochloride.
1Ø9. Composition 1Ø6 wherein the basic amino acid is arginine sulfate.
1Ø10. Composition 1Ø6 wherein the basic amino acid is arginine bicarbonate.
1Ø1.1. Any of the preceding compositions wherein a salt of the basic amino acid is formed in situ in the formulation by neutralization of the basic amino acid with an acid or a salt of an acid.
1Ø12. Any of the preceding compositions wherein the salt of the basic amino acid is formed by neutralization of the basic amino acid to form a premix prior to combination with the fluoride salt.
1Ø13. Any of the preceding compositions wherein the basic amino acid is present in an amount corresponding to about 0.1 --- 20%, e.g., about 1 wt. % to about 10 wt.
% of the total composition weight, the weight of the basic amino acid being calculated as free base form.
1.Ø14. Composition 1.Ø1 1. wherein the basic amino acid is present in an amount of about 7.5 wt. I ofthe total composition fight.
1..03.15. Cor1Ø1 ar i.: acid is present in an amour f 1Ø16. C._>r ro acid 3.75 wt. %
1Ø17. Compositi= 1Ø1 1 to iv O rcid In an amount of about l.. 5 wt. % of th 1Ø15. Any of the preceding compositions wherein the fluoride salt is stannous fluoride, sodiurrt fluoride, potassium fluoride. sodium monofluorophosphate_ sodium fluorosilicate, : '-octadec v ltrimethvlend ia nine i ;ti,NN'-ammonium Ouorosilicate, amine fluoride (e.g..
tris(2-ethanot)-dihydrotluoride'). amr oniurn fluoride, titanium fluoride, hexaf u.orosulfate, and combinations thereof.
1Ø19. Any of the preceding compositions wherein the fluoride salt is a fluorophosphate.
1Ø20. Any of the preceding composition wherein the fluoride salt is sodium monofluorophosphate.
1Ø21. Any of the preceding compositions where the fluoride salt is sodium fluoride.
1Ø21 Any of the preceding compositions wherein the fluoride salt is present in an amount of about 0.01 wt. % o to about 2 wt. % of the total composition weight.
1.023. Any of the preceding compositions wherein the fluoride salt provides fluoride ion in an amount of about 0.1. to about 0.2 wt. % of the total composition weight.
1Ø24. Any of the preceding compositions wherein the soluble fluoride salt provides fluoride ion in an amount of from about 50 to 10,000 ppm.
1Ø25. Any of the preceding compositions which is a mouthwash having 100 to about 250 ppm available fluoride ion.
1Ø26. Any of the preceding compositions which is a dentifrice having about 750 to 2000 ppm available fluoride ion.
1Ø2-7. Any of the preceding compositions wherein the composition comprises 750 to 2000 ppm fluoride ion.
1.Ø25. Any of the preceding compositions wherein the composition comprises .000 to 1500 ppm fluoride ion.
1Ø29. Any ofthe preceding compositions wherein the composition comprises about 1450 ppm fluoride ion.
_030_ Any ;t the. pH is r=
9. e.
Ø3 g . An oft! ie P1po . `s t w pH is _ ')out ,.. tt 7.4.
1Ø32. Any of he preceding compositions wherein the pH is --- n ab- a ,.J
about 1Ø33. Any of the preceding compositions wherein the pH is approximately neutral.
1Ø34. Any of the preceding compositions further comprising an abrasive or particulate.
1Ø35, The immediately preceding composition wherein the adhesive or particulate is selected from sodium bicarbonate, calcium phosphate (e.g., dicalcium phosphate dihydrate), calcium sulfate, precipitated calcium carbonate, silica (e.g..
hydrated silica), iron oxide, aluminum oxide, perlite, plastic particles, e.g., polyethylene, and combinations thereof.
1,0.36. The immediately preceding composition wherein the abrasive or particulate is selected from a calcium phosphate (e.g., dicalcium phosphate dihydrate).
calcium sulfate, precipitated calcium carbonate, silica (e.g., hydrated silica), and combinations thereof.
1.037. Any of the preceding compositions comprising an abrasive in an amount of about 15 wt. % to about 70 wt. % of the total composition weight.
1Ø38. Any of the preceding compositions comprising a small particle abrasive fraction of at least 5% having a d50 of <5 micrometers.
1Ø39. Any of the preceding compositions having a RDA of less than 150, e.g., about 40-140.
1Ø40. Any of the preceding compositions wherein the anionic surfactant is selected from a. water-soluble salts of higher fatty acid monoglyceride monosulfates (e.g., the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids such as sodium N-methyl N-cocoyl taurate, sodium cocomo-glyceride sulfate), h. higher alkyl sulfates, e.g., sodium lauryl sulfate, c. higher alkyl-ether sulfates, e.g., of formula CH.~(CfH-;mCf1-(OCfI-Cf ~),OSO5 ., wherein in is 6-16, e.g:., .10, n is 1-6, e.g., 2, d urn ianreth-2 sodi.n ~.~ , 0.,:: _..w `h as sodium laurvi ~jurii ( ~j t~E ~.~~1 v. htt 3` [[ F~~ ~=~~~ 1 ";- =i:- ie5.+ I `'-1 I
sulfeacetate), higher fatty acid esters of 1,2 dihydroxy propane sulfonate, sulfocolaurate (N-2-ethyl laurate potassium sulfoacetamide) and sodium lauryl sarcosinate), f. and mixtures thereof By "higher alkyl" is meant, e.g., G--'0 alkyl, In particular embodiments. the anionic surfactant is selected from sodium lauryl sulfate and sodium ether lauryl sulfate.
1Ø41. Any of the preceding compositions wherein the anionic surfactant is selected from sodium lauryl sulfate, sodium ether lauryl sulfate, and mixtures thereof.
1Ø42. Any of the preceding compositions wherein the anionic surfactant is present in an amount of from about 0.3% o to about 4.5% by weight.
1Ø43. Any of the preceding compositions additionally comprising surfactants selected from cationic, zwitterionic, and nonionic surfactants, and mixtures thereof.
1Ø44. Any of the preceding compositions comprising at least one humectant.
1Ø45. Any of the preceding compositions comprising at least one humectant selected from glycerin, sorbitol and combinations thereof.
1Ø46. Any of the preceding compositions comprising xylitol.
1Ø47. Any of the preceding compositions comprising at least one polymer.
1Ø4$. Any of the preceding compositions comprising at least one polymer selected from polyethylene glycols, polyvinyimethyl ether malefic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum), and combinations thereof.
1Ø49. Any of the preceding compositions comprising gum strips or fragments.
1Ø50. Any of the preceding compositions comprising f lavorinsg, fragrance andi.or coloring.
1Ø51, Any. of the preceding scions, %
1Ø52. ... l .. .. i._~ tip .- 1 i r -V e carvac.'oi, citral, hinoi.. tol, catechol, n ley 1 e._ `ar4 ~,. __il n = :3i1 to , e pi `ecl in, gallic acid, mis yak extract, sea-buckthorn c r;a ?. bisguanide antiseptics chlorhexidine. alexidine or octenidine'), quaternary ammonium compounds (e.g., cetylpyridinium chloride (CPC), benzalkonium chloride, tetradecylpyridinium chloride (TPC), N-tetradecy 1-4-ethy lpy rid ini um chloride (TD ~OL) i~
phenolic antiseptics, hexetidine, octenidine, sanguinarine, povidone iodine, delmopinol, salilluor, metal ions (e.g.- zinc salts, for example, zinc citrate, stannous salts, copper salts, iron salts). sanguinarine, propolis and oxygenating agents (e.g.. hydrogen peroxide, buffered sodium peroxy borate or peroxycarbonate), phthalic acid and its salts, monoperthalic acid and its salts and. esters, ascorbyl stearate, oleoyl sarcosine, alkyl sulfate, dioctyl sulfosuccinate, salicylanilide, domiphen bromide, delmopinol.
octapinol and other piperidino derivatives, nicin preparations, chlorite salts; and mixtures of any of the foregoing.
1Ø53. Any of the preceding compositions comprising an anti-inflammatory compound, e.g., an inhibitor of at least one of host pro-inflammatory factors selected from matrix metal loprotei nases (MMP's), cyclooxytgenases (COX), PG17, interleukin 1 (IL-1), II--1(l converting enzyme (ICE), transforming growth factor I (TGF-3I). inducible nitric oxide synthase (iNYOS). hyaluronidase, cathepsins, nuclear factor kappa B (NF- B), and IL-I
Receptor Associated Kinase (IRAK), eg, selected from aspirin. ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, aspirin, ketoprofen, piroxicam, meclofenamIc acid, nordihydoguaiarctic acid, and mixtures thereof 1Ø54. Any of the preceding compositions comprising an antioxidant, e.g., selected from the group consisting of Co-enzyme Q10, PQQ. Vitamin C, Vitamin E, Vitamin A.
anethole-dithiothione, and mixtures thereof.
1Ø55. Any of the preceding compositions wherein the anti-microbial is poorly soluble.
1Ø56. Any of the preceding compositions comprising triclosan.
1Ø57. Any of the preceding compositions comprising triclosan and xylitol.
1Ø58. Any of the preceding compositions comprising triclosan, xylitot, and precipitated calcium carbonate.
p antib c 1Ø59. Any of of 0.01 - 5 wt. ie , ._.r 1p - i' i- weight.
1Ø60. Any of the i ccding compositions comprising triclosan in an aTf oui:.
wt. percent (e tfl i )-:i`IC7~ t.
0.3% of the total composition weight.
1Ø62. Any of the preceding compositions comprising a whitening agent.
1Ø63. Any of the preceding compositions comprising a whitening agent selected from a whitening active selected from the group consisting of peroxides. metal ch[orites, perborates, percarbonates. peroxyacids, hy=poch.lorites, and combinations thereof 1Ø64. Any of the preceding compositions comprising hydrogen peroxide or a hydrogen peroxide source, e.g., urea peroxide or a peroxide salt or complex (e.g., such as peroxyphosphate. peroxycarbonate, perborate. peroxysilicate, or persulphate salts, for example calcium peroxyphosphate. sodium perborate, sodium carbonate peroxide, sodium peroxvphosphate. and potassium persulfate).
1Ø65. Any of the preceding compositions further comprising an agent that interferes with or prevents bacteria] attachment, e.g., solbrol or chitosan.
1Ø66. Any of the preceding compositions further comprising a source of calcium and phosphate selected from (i) calcium-glass complexes, e.g., calcium sodium phosphosilicates, and (ii) calcium-protein complexes, e.g., casein phosphopeptide-amorphous calcium phosphate.
1Ø67. Any of the preceding compositions further comprising a soluble calcium salt. e.g., selected from calcium sulfate, calcium chloride, calcium nitrate, calcium acetate, calcium lactate, and combinations thereof.
1Ø68. Any of the preceding compositions further comprising a physiologically acceptable potassium salt, e.g., potassium nitrate or potassium chloride, in an amount ef'lective to reduce dentinal sensitivity.
1Ø69. Any of the preceding compositions comprising from about 0.1 % to about 7.5 o of a physiologically acceptable potassium salt, e.g., potassium nitrate and./or potassium chloride.
1 .C.70. DA of the nr .: d oan Rio, which i a . .,,1 cr.>rtpr. :
iÃ
--.0111c Sur ..t .,.t. 1'- .
monofluorn or soy iumti fiu e j j).71. Any of tf,~ preceding con ti tt 3 ") ;li L: th oral cal itti.
e,-- with brushing, to reduce dry,' m; o 11 ~j 11 _~ M r ion cif hydrating effects. and optionally to (i) reduce or inhibit formation of dental caries.
e.g., caries which result from reduced saliva flow and dry mouth, (ii) reduce, repair or inhibit early enamel lesions, e.g.. as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM), (iii) reduce or inhibit demineralization and.
promote remineralization of the teeth, (iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial hiof lm formation in the oral cavity, (x) raise and~'or maintain plaque pH at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xiii) enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, and/or (xiv) reduce erosion of the teeth, (xv) whiten the teeth. (xvi) immunize the teeth against cariogenic bacteria. (xvii) clean the teeth and oral cavity, and (xviii) reduce steep disruption due to dry mouth.
1Ø72. A composition obtained or obtainable by combining the ingredients as set forth in any of the preceding compositions.
1Ø73. Any ofthe preceding compositions in a form selected from snouthrinse, toothpaste, tooth get, tooth powder, non-abrasive gel, mousse, foam, mouth spray, lozenge, oral tablet, dental implement, and pet care product.
1Ø74. Any of the preceding compositions wherein the composition is toothpaste.
1Ø75. Any of the preceding compositions wherein the composition is a toothpaste optionally further comprising one or more of one or more of water, abrasives, surfactants, foaming agents. vitamins, polymers, enzymes, humectantas, thickeners, antimicrobial agents, preservatives, flavorings. colorings and/or combinations thereof.
1Ø76. Any of the preceding compositions 1.0 - 1Ø72 wherein the composition is a mouthwash.
1Ø77. Any of the preceding compositions 1.0 - 1Ø72 wherein the composition is a the-i 10.7. r . -,i (00091 Levels of active ingredients will vary based on the nature of the deliver.
the particular active. For example. the basic amino acid may be present at levels fro:`., rr o about 0.1 to about 20 wt %(expressed as weight of free base), e.g., about 0.1 to about 3 wt %
for a mouthriuse, about I to about 10 wt % for a consumer toothpaste or about 7 to about 20 wt % for a professional or prescription treatment product. Fluoride may be present at levels of, e.g,, about 25 to about 25.000 ppm, for example about 25 to about 250 ppm for a mouthrinse, about 750 to about 2,000 ppm for a consumer toothpaste, or about 2,000 to about 25.000 ppm for a professional or prescription treatment product. Levels of antibacterial will vary similarly. with levels used in toothpaste being e.g., about 5 to about 15 times greater than used in mouthrinse. For example, a triclosan mouthrinse may contain, e.g., about 0.03 wt % triclosan while a triclosan toothpaste may contain about 0.3 wt %
triclosan.
100101 The present invention also includes Method 2Ø a method for treating, inhibiting or relieving dry- mouth comprising introducing into the oral cavity to a patient in need thereof, e.g., suffering from dry mouth, an oral care composition comprising a basic amino acid in free or salt form, e.g., any one of compositions 1.0 ---- 1Ø78.
100111 Additional embodiments of the present invention also include the following methods:
2.1 Of method 2Ø wherein the method is also effective (i) reduce or inhibit formation of dental caries, (ii) reduce, repair or inhibit early enamel lesions. e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (fCM), (iii) reduce or inhibit demineralization and promote remineralization of the teeth.
(iv) reduce hypersensitivity of the teeth, (v) reduce or inhibit gingivitis, (vi) promote healing of sores or cuts in the mouth, (vii) reduce levels of acid producing bacteria, (viii) to increase relative levels of arginolytic bacteria, (ix) inhibit microbial biofilm formation in the oral cavity, (x) raise and/or maintain plaque pl-I at levels of at least pH 5.5 following sugar challenge, (xi) reduce plaque accumulation, (xiii) enhance systemic health, including cardiovascular health, e.g., by reducing potential for systemic infection via the oral tissues, and/or (xiv) reduce erosion of the teeth, and/or (xv) clean the teeth and oral cavity.
2.2 Of methods 2.0 or 2.2 wherein the composition comprises at least 7.5%
argini.ne.
2.3 Of methods 2.0 --- 2.2 wherein the composition comprises at least 1.0%
arginine bicarbonate.
2. 2,0 ofa hurnectaut, 2.5 O .:, 2,4 2, Of'r. _ t+-:3 2.0 2.whc'f 2.7 Of met hods 2.0 - 2.6 wherein the pe~tient l ~ L.1I rood stuff as a result ofdrv mouth.
2.g Of methods 2.0 -2.7 wherein the patient has difficulty swallowing as a result ofdry mouth.
2.9 Of methods 2.0 - 2.8 wherein the patient has speech difficulties as a result of dry mouth.
2.10 Of methods 2.0 --2,9 wherein the patient also suffers from opportunistic infection of the tongue as a result of dry mouth.
2.11 Of methods 2.0 - 2.10 wherein. dry mouth is caused by a disease.
2.12 Of methods 2.0 -2. 11 wherein the patient is being treated with a medicament, said medicament causing said dry mouth.
2.13 Of methods 2.0 - 2.12 wherein dry mouth is chronic.
2.14 Of methods 2.0 - 2.13 wherein the composition comprises from about 7r.5 o to about 25.0 % arginine.
2.15 Of methods 2.0 - 2,14 wherein the composition is a dentifrice.
2.16 Of methods 2.0 --- 2.15 wherein the composition is a toothpaste.
2.1.7 Of methods 2.0 - 2.16 wherein the composition is a gel.
2.18 Of methods 2.0 - 2.17 wherein the composition is applied in the oral cavity with a tooth brush.
2.19 Of methods 2.0 -- 2.15 wherein the composition is a mouth wash.
2.20 Of methods 2.0 - 2.19 wherein the patient performs the method more than once a day.
2.21 Of methods 2.0 -- 2.20 wherein the patient performs the method daily.
100121 The present invention also contemplates the use of a basic amino acid in free or salt form, e.g., arginine, e.g., as provided in any of compositions 1.0 -1Ø75, for the treatment, amelioration, inhibition, and/or prevention. of dry mouth.
100131 The present invention further provides the use of a basic amino acid, in free or salt form, for the manufacture of a medicament for treating, ameliorating, inhibiting or preventing drys mouth.
t t3 t t [_, 1 -rov?des bdsc d, in free or szf a -- tfi.
y 100151 it r_, ~; ;tad ctm r prevention, era iu; m11 nt, I.inhihitic o ':.ef'. tomnia in a patient suffering ti' :relroa . In one embodiment, the patient. suffers from, or is predisposed to xerostomia h"
sir injury. In another embodiment, the patient suffers from, or is predisposed to xerostomia by treatmmnent(s) of medicaments which cause xerostomia. wherein the dry mouth is a side effect of the medicament.
100161 The term "treat" or "ameliorate" is used herein to mean that administration of a composition of the present invention mitigates a condition in the patient, preferably a mammal, more preferably, a human.
(00171 The term "inhibit" is used herein to mean that administration of a composition of the present invention delays the onset of a condition, e.g., by 6 hours, 12 hours. 24 hours, 48 hours, or 96 hours following the administration of the composition.
[00181 The term "prevent" does not imply that a particular condition will be completely avoided in the future, rather, that the particular condition will be avoided until the patient is able to administer the compositions of the present invention at a second time point, e.g., within 12 hours, 24 hours, 48 hours, or 96 hours of an initial administration.
100191 Without intending to be fund by a particular theory, it is hypothesized that a significant factor in the beneficial effect of arginine is that arginine may be metabolized by certain types of bacteria, e.g., S. sanguis which are not cariogenic and which compete with cariogenic bacteria such as S. mulans, for position on the teeth and in the oral cavity. The arginolytic bacteria can use arginine and other basic amino acids to produce ammonia, thereby raising the p1l of their environment, while cariogenic bacteria metabolize sugar to produce lactic acid, which tends to lower the plaque pl-I and demineralize the teeth, ultimately leading to cavities. It is believed that regular use of a Composition of the Invention, over time, will lead to a relative increase in the arginolytic bacteria and a relative decrease in the cariogenic bacteria, resulting in a higher plaque pl-I
(notwithstanding that the Composition of the Invention is itself generally pH neutral, the basic amino acid having been neutralized by an inorganic oxoacid). It is believed. that this pH-raising effect may be accomplished in compositions which are substantially free of fluoride. It is also believed that this pff-raising effect may be mechanistically separate from and complementary to the effect of fluoride in promoting remineralization and strengthening the to.--,.h enamel.
[00201 Conce i _ r. t t -re c{,. , 'r nr _ ZL MY be õ
Z;A b,_7 ind by then is Y ;Igher le~~ i ~'_ 1 I
7.50%. that is, from about r.5 to about 5 =fl, from about 8 about 20%. from e -t, i 9% to about 15%, or about 10% coat teeth, gums, and/or the oral cavity, leaving a perception that the mouth has been moisturized or hydrated.
100211 Compositions of the present invention may be in the form of a dentifrice comprising additional ingredients selected from one or more of'water, abrasives, surfactants, foaming agents, vitamins, polymers, enzymes, humeetants, thickeners, antimicrobial agents. preservatives, flavorings, colorings and/or combinations thereof.
100221 The basic amino acids which can be used in the compositions and methods of the invention include not only naturally occurring basic amino acids, such as arginine, lysine, and histidine, but also any basic amino acids having a carboxyl group and an amino group in the molecule, which are water-soluble and provide an aqueous solution with a pli of 7 or greater. Accordingly, basic amino acids include, but are not limited to, arginine, lysine, citrullene, ornithine, creative, histidine, diaminobutanoic acid, diaminoproprionic acid, salts thereof or combinations thereof. In a particular embodiment, the basic amino acids are selected from arginine, citrullene, and ornithine. In certain embodiments, the basic amino acid is arginine, for example, L,-arginine, or a salt thereof.
100231 The compositions of the invention are intended for topical use in the mouth and so salts for use in the present invention should be safe for such use, in the amounts and concentrations provided. Suitable salts include salts known in the art to be pharmaceutically acceptable salts are generally considered to be physiologically acceptable in the amounts and concentrations provided. Physiologically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic acids or bases, for example acid addition salts formed by acids which form a physiological acceptable anion, e.g., hydrochloride or bromide salt, and base addition salts formed by bases which form a physiologically acceptable cation, for example those derived from alkali metals such as potassium and sodium or alkaline earth metals such as calcium and magnesium.
Physiologically acceptable salts may be obtained using standard procedures known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically, acceptable anion.
~ a sic amino acid present in an amount of about 7,5 ~002~f Ire various ~:nibc~e_ `:.-. i-s, 1 % ~3,ttc w i_ '.a Wit. , F, A e about 1. 5wt. or ". 5 wt.
of 100251 The oral care may further include one or more fluoride on sources, e. ,., soluble fluoride salts. A wide variety of fluoride ion-vieldin.g materials can be employed as sources of soluble fluoride in the present compositions, and such materials are known to those of skill in the art, Examples of suitable fluoride ion-yielding materials are found in U.S. Pat. No. 3,535,421, to Briner et al.; U.S. Pat, No. 4,885.155.
to Parran, Jr. et a.. and U.S. Pat.' o. 3.678,154, to Widder et al., incorporated herein by reference.
100261 Representative fluoride ion sources include, but are not limited to, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate. ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof. In certain embodiments the fluoride ion source includes stannous fluoride, sodium fluoride, sodium monofluorophosphate as well as mixtures thereof.
100271 In certain embodiments, the oral care composition of the invention may also contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 25 ppm to 25,000 ppm of fluoride ions, generally at least about 500 ppm, e.g., about 500 to about 2000 ppm, e.g.. about 1000 to about 1600 ppm, e.g., about 1450 ppm.
The appropriate level of fluoride will depend on the particular application. A
mouthwash, for example, would typically have about 100 to about 250 ppm fluoride. A
toothpaste for general consumer use would typically have about 1.000 to about 1.500 ppm, with pediatric toothpaste having somewhat less. A dentifrice or coating for professional application could have as much as 5,000 or even 25,000 ppm fluoride.
100281 In certain embodiments, the oral care composition of the invention may contain a source of fluoride ions or fluorine-providing ingredient in amounts sufficient to supply about 100 ppm to 10,000 ppm of fluoride ions, e.g., 1000-2000 ppm..
100291 The Compositions of the Invention may comprise a calcium phosphate abrasive, e.g., tricalcium phosphate (Ca-,(1'O)) ), hydroxyapatite (Ca, (PO4)6(OH)2), or dicalcium phosphate dihydrate (CaFIP04 ; = 2H_O. also sometimes referred to herein as DiCal) or calcium pyrophosphate.
100301 The compositions may include one or more additional abrasives known by those of skill in the art, for example silica abrasives such as precip tatccd silicas having a mean particle size of up to about 20 microns, such as Icodent I 1 marketed by J. M.
Iluber.
==i , . m'.~ipl3Lls~,l __C;. lil Sp hate.
;r t ~reraii have n avera e pa tici,~ iz ut 30 micron.
about between 5 and about 15 microns. The silica s,~3rasiv'es can be from precipitated silica or silica gels, such as the silica xerogels described in U.S. Pat. No.
3,538,230. to fader et at.
and U.S. Pat. No. 3,862,307, to Digiulio, both incorporated herein by reference. Particular silica xerogels are marketed under the trade name Syloid`' by the W. R. Grace & Co., Davison Chemical Division. The precipitated silica materials include those marketed by the .l. M. Huber Corp. under the trade name Zeodentt, including the silica carrying the designation Zeodent 115 and 119. These silica abrasives are described in [U.S.
Pat. No.
and U.S. Pat. No. 3,862,307, to Digiulio, both incorporated herein by reference. Particular silica xerogels are marketed under the trade name Syloid`' by the W. R. Grace & Co., Davison Chemical Division. The precipitated silica materials include those marketed by the .l. M. Huber Corp. under the trade name Zeodentt, including the silica carrying the designation Zeodent 115 and 119. These silica abrasives are described in [U.S.
Pat. No.
4.340,583, to \Vason, incorporated herein by reference.
100321 In. certain embodiments, abrasive materials useful in the practice of the oral care compositions in accordance with the invention include silica gels and precipitated amorphous silica. having an oil absorption value of about less than 100 cc!l00 g silica and in the range of about 45 cc/100 g to about 70 cc/100 g silica. Oil absorption values are measured using the ASIA Rub-Out Method D281. In certain embodiments, the silicas are colloidal particles having an average particle size of about 3 microns to about 12 microns, and about 5 to about 10 microns.
100331 In particular embodiments, the particulate or abrasive materials comprise a large fraction of very small particles, e.g., having a d50 less than about 5 microns, for example small particle silica (SPS) having a d50 of about 3 to about 4 microns, for example Sorbosi AC41t (Ineos). Such small particles are particularly useful in formulations targeted at reducing hypersensitivity. The small particle component may be present in combination with a second larger particle abrasive. In certain embodiments. for example, the formulation comprises about 3 to about 8% SPS and about 25 to about 45% of a conventional abrasive.
100341 Low oil absorption silica abrasives particularly useful in the practice of the invention are marketed under the trade designation Sylodent XWA by Davison Chemical Division of W.R. Grace & Co., Baltimore, old. 21203. Sylodent 650 XWA ,, a silica hydrogel composed of particles of colloidal silica having a water content of about 29% by weight averaging about 7 to about 10 microns in diameter, and an oil absorption of less than about 70 cc/100 g of silica is an example of a. low cil absorption silica abrasive useful -le Cal'- ~= r''.vt e present nvi' tion. The in the oral (m re. composition i I
ilk i on l r. ` n CL[zwr 45%
100351 The oral _r compositions of the invention also may include an agent to increase the amount of foam that is produced. when the oral cavity is brushed. Such agents are known to those of skill in the art. Illustrative examples of agents that increase the amount of foam include, but are not limited to poyoxyethy lene and certain polymers including, but not limited to, alginate polymers.
100361 The polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care carrier component of the present invention.
Doty oxyethvlene is also commonly known as polyethylene glycol ("PEG") or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of 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 about 800.000 to about 1,000,000.
Polyox is the trade name for the high molecular weight polyoxyethylene produced by Union Carbide.
100371 The polyoxyethylene may be present in an amount of about 1% to about 90%, in one embodiment about 5% to about 50% and in another embodiment about 10% to about 20% by weight of the oral care carrier component of the oral care compositions of the present invention. The dosage of foaming agent in the oral care composition (i.e., a single dose) is about 0.01 to about 0.9 % by weight, about 0.05 to about 0.5% by weight, and in another embodiment about 0. 1 to about 0.2 % by weight.
[00381 Another agent optionally included in the oral care composition of the invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants are those which are reasonably stable throughout a wide pH range, for example, anionic, cationic, nonionic or zwitterionic surfactants. Suitable surfactants are described more fully, for example, in U.S.
Pat. No. 3,959,458, to Agricola et al.; U.S. Pat. No. 3,937,807, to Haefele;
and U.S. Pat. No.
4,051,234. to Gieske et al., which are incorporated herein by reference. A
preferred surfactant is sodium lauryl sulfate.
[00391 The surfactant or mixtures of compatible surfactants can be present in the compositions of the present invention in about 0.1 % to about 5.0%, in another embodiment about 0.3% to about 3.0% and in another embodiment about 0.5% to about 2.0% by weight of the total composition.
E00401 lbe c'ril c =are compo~it'tm 4th,? invention n :l ?a, ttC a flavoring agent.
e,I
i ftl! ;arose - of tti C as we! _ , %i 1 .and similar compos ~min at a concentration cf about 0.1 to about 5',, h_ ~. _ i_ ht and abt iu =u.5 to about .% by weight. The dosage of flavoring agent in the individual oral care composition dosage (i.e.. a single dose) is about 0.001 to 0.05 i by weight and in another embodiment about 0.005 to 0.015 % o by weight.
100411 The oral care compositions and methods of the invention also may optionally include one or more chelating agents able to complex calcium found in the cell wails ofthe bacteria, Binding of this calcium weakens the bacterial cell wall and augments bacterial lysis. Chelating agents are well known by those of skill in the art, e.g., soluble pyrophosphates, either in hydrated or unhydrated forms. An effective amount of pyrophosphate salt useful in the present composition is generally enough to provide at least 1.0 wt. % pyrophosphate ions, about 1.5 wt. % to about 6 wt. %, about 3.5 wt.
% to about 6 wt. % of such ions.
[0042] The oral care compositions or methods of the invention also optionally include one or more polymers, which are known by those of skill in the art. Such polymers may include polyethylene glycols, polyvinylmethyl ether maleic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum). Polymers suitable for use may include Gantrez AN l39(M.W. 500,000), AN 119 (MM. 250,000) and S-97 Pharmaceutical Grade (M.W.
70,000), of GAF Chemicals Corporation. Suitable polymers may also include homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalykane sulfonic acids such as 2-acrvlamide 2 methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid, incorporated herein by reference, Another useful class of polymeric agents includes polyamino acids, particularly those containing proportions of anionic surface-active amino acids such as aspartic acid, glutamic acid and phosphoserine, as disclosed in U.S. Pat. No. 4,866,161. Sikes et al., incorporated herein by reference.
100431 The compositions and methods of the present invention may also comprise thickening material to provide a desirable consistency or to stabilize or enhance the a.u..r o < _ ~F x 'vex s- n z''- s~'o e "
fc;rmlati ~ such "L C
.. `
;i4 such so ] u in_ orporatcJ. Colloidal rn _r_e um aluminum ' ' . . r finely divid.o1 1 component of the thickeniing composition to further improve the composition's it texture. In certain embodiments, thickening agents in an amount of about 0.5%
to about 5.0% by weight of the total composition are used.
100441 The compositions and methods of the present invention may also optionally include one or more enzymes. Useful enzymes include those known by those of skill in. the art. and may include proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases or compatible mixtures thereof Enzymes suitable for use in the present invention are disclosed in U.S. Pat. No. 5.000,939 to faring et al., U.S. Pat. No.
4,991420; U.S. Pat. No. 4,355,0"22; U.S. Pat. No. 4,1.54,815; U.S. Pat. No, 4,058,595; U.S.
Pat. No. 3,991,177; and U.S. Pat. No. 3,696,191 all incorporated herein by reference. An enzyme of a mixture of several compatible enzymes in the current invention constitutes about 0.002% to about 2.0% in one embodiment or about 0.05% to about 1.5% in another embodiment or in yet another embodiment about 0.1 % to about 0.5%.
[00451 Water may also be present in the oral compositions of the invention, Water, employed in the preparation of commercial oral compositions is preferably deionized and free of organic impurities. Water commonly makes up the balance of the compositions, and includes the free water which is added plus that amount which is introduced with other materials such as with sorbitol or any components of the invention.
[0046] The present invention may comprise humectant to prevent the composition 1rom hardening upon exposure to air, and to aid in the hydration of the mouth.
Certain hurnectants can also impart desirable sweetness or flavor to dentifrice compositions. The humectant, on a pure humectant basis, generally includes about 15% to about 70% in one embodiment or about 30% to about 65% in another embodiment by weight of the dentifrice composition.
100471 Suitable humectants include edible polyhydric alcohols such as glycerine, sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of these humectants.
Mixtures of glycerine and sorbitol may be used in certain embodiments as the humectant component of the toothpaste compositions herein.
100481 In addition to the above described components, the embodiments of this invention variety à fzs vz ? 1 der tifri e ingredients som of whic1 r d sC be h to 5,004,59 ".Taje_i; f. S. Pit. var. 3A",)-1 58 A=ri"or`a et a_ ,._ . Pat, No.
3. F, to Ilaefele, all being incorporated herein by reference..
100491 The compositions and methods according to the invention are useful to a method to treat dry mouth, and optionally protect the teeth by facilitating repair and remineralization, in particular to reduce or inhibit formation of dental caries, reduce or inhibit demineralization and promote remineralization of the teeth. reduce hypersensitivity of the teeth, and reduce, repair or inhibit pre-carious lesions of the enamel, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM).
Quantitative light-induced fluorescence is a visible light system that permits early detection of pre-caries lesions in the enamel. Normal teeth fluoresce in visible light;
demineralized teeth do not or do so only to a lesser degree. The area of demineralization can be quantified and its progress monitored. Electrical conductance measurement exploits the fact that the fluid-filled tubules exposed upon demineralization and erosion of the enamel conduct electricity. An increase in the conductance of the patient's teeth therefore may indicate demineralization. The Compositions of the Invention are thus useful in a method to reduce pre-carious lesions of the enamel (as measured by QLF or ECM) relative to a composition lacking effective amounts of fluorine andior arginine.
100501 As such the Compositions of the Invention are useful not only for treating dry mouth, but also for treating other oral conditions in the mouth, and to clean the oral cavity and provide improved methods of promoting oral health.
100511 Enhancing oral health also provides benefits in systemic health, as the oral tissues can be gateways for systemic infections. Good oral health is associated with systemic health, including cardiovascular health. The compositions and methods of the invention provide particular benefits because basic amino acids, especially arginine, are sources of nitrogen which supply NO synthesis pathways and thus enhance microcirculation in the oral tissues. Providing a less acidic oral environment is also helpful in reducing gastric distress and creates an environment less favorable to Heliobacter, which. is associated with gastric ulcers. Arginine in particular is required for high expression of specific immune cell receptors, for example T-cell receptors, so that arginine can enhance an effective irrilnune response. The compositions and methods of the invention are thus useful to enhance systemic health. including cardiovascular health.
100521 Ti". .ct J 'l,-7 ~1 e tll' . õ it tr _ _~.ti h sucn r7` ays and c11_' ?.
100531 .\s used throu Hout. ranges are > d , I -,,)rth lyd d each and every value that is within the range. Any, value within the range .,n be selected as the terminus of the range. In addition. all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls. It is understood that when formulations are described, they may be described in terms of their ingredients, as is common in the art, notwithstanding that these ingredients may react with one another in the actual formulation as it is made, stored and used, and such products are intended to be covered by the formulations described.
100541 The following examples further describe and demonstrate illustrative embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations of this invention as many variations are possible without departing from the spirit and scope thereof. Various modifications of the invention in addition to those shown and described herein should be apparent to those skilled in the art and are intended to fall within the appended claims.
Example ].-.Toothpaste formulation [00551 A toothpaste composition is prepared from the following ingredients to produce a toothpaste having 7.50% wt. arginine.
Deionized Water 7.400 Glycerin 21.000 Carboxymethyl cellulose 0.500 Saccharin 0.250 Basic amino acid salt (arginine bicarbonate) 10.000 Calcium carbonate 29.000 Hydrated silica 31.000 Flavor 0.'50 Color solution (1% FD&C Blue 41) 0.100 Example 2 - Patient study 100561 Eight patients suffering from dry mouth are provided with the composition of <A fPLE 1. The patients are instructed io brush with the composition of FXfz":NIP' E I
hs rvata I 4 mouth :'110r 8.
'010571 Prior to use of the tr uti r from dry mo-iii hole leday:
- four `?`3tient`i also suii- c from dry ii Ps and tC)T LIB t v{} }iÃt3s t u ,.-;ilowino-:: 3 have difficulty eating. talking and sleeping due to dry mouth.
2`l 100581 At day 4, most patients feel the composition hydrates their mouth, and left the mouth feeling comfortable. No patient thinks the composition made the mouth drier. 25%
of patients indicate that the mouth felt smooth. moist. and hydrated.
100591 At day 8, most patients believe the composition provides dry mouth relief. leaving their mouth feeling moist, pleasant and smooth.
Example 3: Artificial Saliva Formulation comprising Artinine [00601 An artificial saliva formulation is prepared from the following ingredients:
RAW MATERIAL WEIGHT %
Deionized Water 96.26815 Xylitol 2.00000 L-Arginine 0.50000 Hydroxyethyl cellulose 0.43000 Flavor 0.40000 Methyl paraben 0.20000 Dibasic potassium phosphate 0.08000 Potassium chloride 0.06200 Potassium phosphate monobasic 0.04300 Calcium chloride dihydrate 0.01000 Magnesium chloride 0.00590 Food colorant 0.00050 Sodium fluoride 0.00045 TOTAL 100.00000
100321 In. certain embodiments, abrasive materials useful in the practice of the oral care compositions in accordance with the invention include silica gels and precipitated amorphous silica. having an oil absorption value of about less than 100 cc!l00 g silica and in the range of about 45 cc/100 g to about 70 cc/100 g silica. Oil absorption values are measured using the ASIA Rub-Out Method D281. In certain embodiments, the silicas are colloidal particles having an average particle size of about 3 microns to about 12 microns, and about 5 to about 10 microns.
100331 In particular embodiments, the particulate or abrasive materials comprise a large fraction of very small particles, e.g., having a d50 less than about 5 microns, for example small particle silica (SPS) having a d50 of about 3 to about 4 microns, for example Sorbosi AC41t (Ineos). Such small particles are particularly useful in formulations targeted at reducing hypersensitivity. The small particle component may be present in combination with a second larger particle abrasive. In certain embodiments. for example, the formulation comprises about 3 to about 8% SPS and about 25 to about 45% of a conventional abrasive.
100341 Low oil absorption silica abrasives particularly useful in the practice of the invention are marketed under the trade designation Sylodent XWA by Davison Chemical Division of W.R. Grace & Co., Baltimore, old. 21203. Sylodent 650 XWA ,, a silica hydrogel composed of particles of colloidal silica having a water content of about 29% by weight averaging about 7 to about 10 microns in diameter, and an oil absorption of less than about 70 cc/100 g of silica is an example of a. low cil absorption silica abrasive useful -le Cal'- ~= r''.vt e present nvi' tion. The in the oral (m re. composition i I
ilk i on l r. ` n CL[zwr 45%
100351 The oral _r compositions of the invention also may include an agent to increase the amount of foam that is produced. when the oral cavity is brushed. Such agents are known to those of skill in the art. Illustrative examples of agents that increase the amount of foam include, but are not limited to poyoxyethy lene and certain polymers including, but not limited to, alginate polymers.
100361 The polyoxyethylene may increase the amount of foam and the thickness of the foam generated by the oral care carrier component of the present invention.
Doty oxyethvlene is also commonly known as polyethylene glycol ("PEG") or polyethylene oxide. The polyoxyethylenes suitable for this invention will have a molecular weight of 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 about 800.000 to about 1,000,000.
Polyox is the trade name for the high molecular weight polyoxyethylene produced by Union Carbide.
100371 The polyoxyethylene may be present in an amount of about 1% to about 90%, in one embodiment about 5% to about 50% and in another embodiment about 10% to about 20% by weight of the oral care carrier component of the oral care compositions of the present invention. The dosage of foaming agent in the oral care composition (i.e., a single dose) is about 0.01 to about 0.9 % by weight, about 0.05 to about 0.5% by weight, and in another embodiment about 0. 1 to about 0.2 % by weight.
[00381 Another agent optionally included in the oral care composition of the invention is a surfactant or a mixture of compatible surfactants. Suitable surfactants are those which are reasonably stable throughout a wide pH range, for example, anionic, cationic, nonionic or zwitterionic surfactants. Suitable surfactants are described more fully, for example, in U.S.
Pat. No. 3,959,458, to Agricola et al.; U.S. Pat. No. 3,937,807, to Haefele;
and U.S. Pat. No.
4,051,234. to Gieske et al., which are incorporated herein by reference. A
preferred surfactant is sodium lauryl sulfate.
[00391 The surfactant or mixtures of compatible surfactants can be present in the compositions of the present invention in about 0.1 % to about 5.0%, in another embodiment about 0.3% to about 3.0% and in another embodiment about 0.5% to about 2.0% by weight of the total composition.
E00401 lbe c'ril c =are compo~it'tm 4th,? invention n :l ?a, ttC a flavoring agent.
e,I
i ftl! ;arose - of tti C as we! _ , %i 1 .and similar compos ~min at a concentration cf about 0.1 to about 5',, h_ ~. _ i_ ht and abt iu =u.5 to about .% by weight. The dosage of flavoring agent in the individual oral care composition dosage (i.e.. a single dose) is about 0.001 to 0.05 i by weight and in another embodiment about 0.005 to 0.015 % o by weight.
100411 The oral care compositions and methods of the invention also may optionally include one or more chelating agents able to complex calcium found in the cell wails ofthe bacteria, Binding of this calcium weakens the bacterial cell wall and augments bacterial lysis. Chelating agents are well known by those of skill in the art, e.g., soluble pyrophosphates, either in hydrated or unhydrated forms. An effective amount of pyrophosphate salt useful in the present composition is generally enough to provide at least 1.0 wt. % pyrophosphate ions, about 1.5 wt. % to about 6 wt. %, about 3.5 wt.
% to about 6 wt. % of such ions.
[0042] The oral care compositions or methods of the invention also optionally include one or more polymers, which are known by those of skill in the art. Such polymers may include polyethylene glycols, polyvinylmethyl ether maleic acid copolymers, polysaccharides (e.g., cellulose derivatives, for example carboxymethyl cellulose, or polysaccharide gums, for example xanthan gum or carrageenan gum). Polymers suitable for use may include Gantrez AN l39(M.W. 500,000), AN 119 (MM. 250,000) and S-97 Pharmaceutical Grade (M.W.
70,000), of GAF Chemicals Corporation. Suitable polymers may also include homopolymers of substituted acrylamides and/or homopolymers of unsaturated sulfonic acids and salts thereof, in particular where polymers are based on unsaturated sulfonic acids selected from acrylamidoalykane sulfonic acids such as 2-acrvlamide 2 methylpropane sulfonic acid having a molecular weight of about 1,000 to about 2,000,000, described in U.S. Pat. No. 4,842,847, Jun. 27, 1989 to Zahid, incorporated herein by reference, Another useful class of polymeric agents includes polyamino acids, particularly those containing proportions of anionic surface-active amino acids such as aspartic acid, glutamic acid and phosphoserine, as disclosed in U.S. Pat. No. 4,866,161. Sikes et al., incorporated herein by reference.
100431 The compositions and methods of the present invention may also comprise thickening material to provide a desirable consistency or to stabilize or enhance the a.u..r o < _ ~F x 'vex s- n z''- s~'o e "
fc;rmlati ~ such "L C
.. `
;i4 such so ] u in_ orporatcJ. Colloidal rn _r_e um aluminum ' ' . . r finely divid.o1 1 component of the thickeniing composition to further improve the composition's it texture. In certain embodiments, thickening agents in an amount of about 0.5%
to about 5.0% by weight of the total composition are used.
100441 The compositions and methods of the present invention may also optionally include one or more enzymes. Useful enzymes include those known by those of skill in. the art. and may include proteases, glucanohydrolases, endoglycosidases, amylases, mutanases, lipases and mucinases or compatible mixtures thereof Enzymes suitable for use in the present invention are disclosed in U.S. Pat. No. 5.000,939 to faring et al., U.S. Pat. No.
4,991420; U.S. Pat. No. 4,355,0"22; U.S. Pat. No. 4,1.54,815; U.S. Pat. No, 4,058,595; U.S.
Pat. No. 3,991,177; and U.S. Pat. No. 3,696,191 all incorporated herein by reference. An enzyme of a mixture of several compatible enzymes in the current invention constitutes about 0.002% to about 2.0% in one embodiment or about 0.05% to about 1.5% in another embodiment or in yet another embodiment about 0.1 % to about 0.5%.
[00451 Water may also be present in the oral compositions of the invention, Water, employed in the preparation of commercial oral compositions is preferably deionized and free of organic impurities. Water commonly makes up the balance of the compositions, and includes the free water which is added plus that amount which is introduced with other materials such as with sorbitol or any components of the invention.
[0046] The present invention may comprise humectant to prevent the composition 1rom hardening upon exposure to air, and to aid in the hydration of the mouth.
Certain hurnectants can also impart desirable sweetness or flavor to dentifrice compositions. The humectant, on a pure humectant basis, generally includes about 15% to about 70% in one embodiment or about 30% to about 65% in another embodiment by weight of the dentifrice composition.
100471 Suitable humectants include edible polyhydric alcohols such as glycerine, sorbitol, xylitol, propylene glycol as well as other polyols and mixtures of these humectants.
Mixtures of glycerine and sorbitol may be used in certain embodiments as the humectant component of the toothpaste compositions herein.
100481 In addition to the above described components, the embodiments of this invention variety à fzs vz ? 1 der tifri e ingredients som of whic1 r d sC be h to 5,004,59 ".Taje_i; f. S. Pit. var. 3A",)-1 58 A=ri"or`a et a_ ,._ . Pat, No.
3. F, to Ilaefele, all being incorporated herein by reference..
100491 The compositions and methods according to the invention are useful to a method to treat dry mouth, and optionally protect the teeth by facilitating repair and remineralization, in particular to reduce or inhibit formation of dental caries, reduce or inhibit demineralization and promote remineralization of the teeth. reduce hypersensitivity of the teeth, and reduce, repair or inhibit pre-carious lesions of the enamel, e.g., as detected by quantitative light-induced fluorescence (QLF) or electrical caries measurement (ECM).
Quantitative light-induced fluorescence is a visible light system that permits early detection of pre-caries lesions in the enamel. Normal teeth fluoresce in visible light;
demineralized teeth do not or do so only to a lesser degree. The area of demineralization can be quantified and its progress monitored. Electrical conductance measurement exploits the fact that the fluid-filled tubules exposed upon demineralization and erosion of the enamel conduct electricity. An increase in the conductance of the patient's teeth therefore may indicate demineralization. The Compositions of the Invention are thus useful in a method to reduce pre-carious lesions of the enamel (as measured by QLF or ECM) relative to a composition lacking effective amounts of fluorine andior arginine.
100501 As such the Compositions of the Invention are useful not only for treating dry mouth, but also for treating other oral conditions in the mouth, and to clean the oral cavity and provide improved methods of promoting oral health.
100511 Enhancing oral health also provides benefits in systemic health, as the oral tissues can be gateways for systemic infections. Good oral health is associated with systemic health, including cardiovascular health. The compositions and methods of the invention provide particular benefits because basic amino acids, especially arginine, are sources of nitrogen which supply NO synthesis pathways and thus enhance microcirculation in the oral tissues. Providing a less acidic oral environment is also helpful in reducing gastric distress and creates an environment less favorable to Heliobacter, which. is associated with gastric ulcers. Arginine in particular is required for high expression of specific immune cell receptors, for example T-cell receptors, so that arginine can enhance an effective irrilnune response. The compositions and methods of the invention are thus useful to enhance systemic health. including cardiovascular health.
100521 Ti". .ct J 'l,-7 ~1 e tll' . õ it tr _ _~.ti h sucn r7` ays and c11_' ?.
100531 .\s used throu Hout. ranges are > d , I -,,)rth lyd d each and every value that is within the range. Any, value within the range .,n be selected as the terminus of the range. In addition. all references cited herein are hereby incorporated by reference in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls. It is understood that when formulations are described, they may be described in terms of their ingredients, as is common in the art, notwithstanding that these ingredients may react with one another in the actual formulation as it is made, stored and used, and such products are intended to be covered by the formulations described.
100541 The following examples further describe and demonstrate illustrative embodiments within the scope of the present invention. The examples are given solely for illustration and are not to be construed as limitations of this invention as many variations are possible without departing from the spirit and scope thereof. Various modifications of the invention in addition to those shown and described herein should be apparent to those skilled in the art and are intended to fall within the appended claims.
Example ].-.Toothpaste formulation [00551 A toothpaste composition is prepared from the following ingredients to produce a toothpaste having 7.50% wt. arginine.
Deionized Water 7.400 Glycerin 21.000 Carboxymethyl cellulose 0.500 Saccharin 0.250 Basic amino acid salt (arginine bicarbonate) 10.000 Calcium carbonate 29.000 Hydrated silica 31.000 Flavor 0.'50 Color solution (1% FD&C Blue 41) 0.100 Example 2 - Patient study 100561 Eight patients suffering from dry mouth are provided with the composition of <A fPLE 1. The patients are instructed io brush with the composition of FXfz":NIP' E I
hs rvata I 4 mouth :'110r 8.
'010571 Prior to use of the tr uti r from dry mo-iii hole leday:
- four `?`3tient`i also suii- c from dry ii Ps and tC)T LIB t v{} }iÃt3s t u ,.-;ilowino-:: 3 have difficulty eating. talking and sleeping due to dry mouth.
2`l 100581 At day 4, most patients feel the composition hydrates their mouth, and left the mouth feeling comfortable. No patient thinks the composition made the mouth drier. 25%
of patients indicate that the mouth felt smooth. moist. and hydrated.
100591 At day 8, most patients believe the composition provides dry mouth relief. leaving their mouth feeling moist, pleasant and smooth.
Example 3: Artificial Saliva Formulation comprising Artinine [00601 An artificial saliva formulation is prepared from the following ingredients:
RAW MATERIAL WEIGHT %
Deionized Water 96.26815 Xylitol 2.00000 L-Arginine 0.50000 Hydroxyethyl cellulose 0.43000 Flavor 0.40000 Methyl paraben 0.20000 Dibasic potassium phosphate 0.08000 Potassium chloride 0.06200 Potassium phosphate monobasic 0.04300 Calcium chloride dihydrate 0.01000 Magnesium chloride 0.00590 Food colorant 0.00050 Sodium fluoride 0.00045 TOTAL 100.00000
Claims (32)
1. A method to treat, ameliorate, inhibit, or prevent dry mouth comprising administering to the oral cavity of a patient in need thereof a composition comprising a basic amino acid, in free or salt form.
2. The method of claim 1 wherein the basic amino acid is arginine,
3. The method of claim 2 wherein the arginine is in the form of arginine bicarbonate.
4. The method of claim 1, 2 or 3 wherein the composition further comprises one or more of a. a calcium ion source, b. a phosphate ion source, c. a potassium ion source, d. a magnesium ion source, e. a fluoride source;
f. a flavorant which promotes saliva flow;
g. a polyol humectant;
h. and combinations thereof,
f. a flavorant which promotes saliva flow;
g. a polyol humectant;
h. and combinations thereof,
5. The method of any of the preceding claims wherein the patient is predisposed to dry mouth.
6. The method of any of the preceding claims wherein the patient is suffering from dry mouth.
7. The method of any of the preceding claims wherein the patient has difficulty masticating food as a result of dry mouth.
8. The method of any of the preceding claims wherein the patient has difficulty swallowing as a result of dry mouth.
9. The method of any of the preceding claims wherein the patient has speech difficulties as a result of dry mouth.
10. The method of any of the preceding claims wherein the patient also suffers from opportunistic infection of the tongue as a result of dry mouth.
11. The method of any of the preceeding claims wherein dry mouth is caused by a disease.
12. The method of any of the preceding claims wherein the patient is being treated with a medicament, said medicament causing said dry mouth.
13. The method of any of the preceding claims wherein dry mouth is chronic.
14. The method of any of the preceding claims wherein the composition is a dentifrice.
15. The method of any of the preceding claims wherein the composition is a mouth rinse.
16. The method of claim 15 wherein the mouthrinse is an artificial saliva comprising ions selected from calcium, phosphate, potassium, magnesium, and combinations thereof.
17. The method of any of the preceding claims which reduces or inhibits development of caries.
18. An artificial saliva comprising arginine in free or salt form, together with one or more of a. a calcium ion source, b. a phosphate ion source, c. a potassium ion source, d. a magnesium ion source, e, a fluoride source;
f. a flavorant which promotes saliva flow; and/or g. a polyol humectant.
f. a flavorant which promotes saliva flow; and/or g. a polyol humectant.
19. Use of a basic amino acid, in free or salt form. for the manufacture of a medicament for treating, ameliorating, inhibiting or preventing dry mouth.
20. The use of claim 19 wherein the basic amino acid is arginine.
21. The use of claim 20 wherein the arginine is in the form of arginine bicarbonate.
22. The use of any one of claims 19 to 21 in a medicament which further comprises one or more of a. a calcium ion source, b. a phosphate ion source, c. a potassium ion source, d. a magnesium ion source, e. a fluoride source-, f. a flavorant which promotes saliva flow;
g. polyol humectant;
h. and combinations thereof.
g. polyol humectant;
h. and combinations thereof.
23. The use of claim 22 wherein the medicament is a dentifrice.
24. The use of claim 22 wherein the medicament is a mouth rinse.
25. The use of claim 24 wherein the mouthrinse is an artificial saliva comprising ions selected from calcium, phosphate, potassium and combinations thereof.
26. A basic amino acid, in free or salt form, for use in the treatment, amelioration.
inhibition or prevention of dry mouth.
inhibition or prevention of dry mouth.
27. The basic amino acid of claim 26 wherein the basic amino acid is arginine.
28. The basic amino acid of claim 27 wherein the arginine is in the form of arginine bicarbonate.
29. The basic amino acid of any one of claims 26 to 28 in a composition which further comprises one or more of a. a calcium ion source, b. a phosphate ion source, c. a potassium ion source, d. a magnesium ion source, e. a fluoride source;
f. a flavorant which promotes saliva flow;
g. a polyol humectant;
h. and combinations thereof,
f. a flavorant which promotes saliva flow;
g. a polyol humectant;
h. and combinations thereof,
30. The basic amino acid of claim 29 wherein the composition is a dentifrice.
31. The basic amino acid of claim 29 wherein the composition is a mouth rinse.
32. The basic amino acid of claim 31 wherein the mouthrinse is an artificial saliva comprising ions selected from calcium, phosphate, potassium, magnesium, and combinations thereof.
Applications Claiming Priority (13)
| Application Number | Priority Date | Filing Date | Title |
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| US2743508P | 2008-02-08 | 2008-02-08 | |
| US2743208P | 2008-02-08 | 2008-02-08 | |
| US2742008P | 2008-02-08 | 2008-02-08 | |
| US2743108P | 2008-02-08 | 2008-02-08 | |
| US61/027,435 | 2008-02-08 | ||
| US61/027,420 | 2008-02-08 | ||
| US61/027,432 | 2008-02-08 | ||
| US61/027,431 | 2008-02-08 | ||
| US2743808P | 2008-02-09 | 2008-02-09 | |
| US2744208P | 2008-02-09 | 2008-02-09 | |
| US61/027,442 | 2008-02-09 | ||
| US61/027,438 | 2008-02-09 | ||
| PCT/US2009/033291 WO2009100265A2 (en) | 2008-02-08 | 2009-02-06 | Compositions and methods for the treatment of xerostomia |
Publications (2)
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| CA2711263A1 true CA2711263A1 (en) | 2009-08-13 |
| CA2711263C CA2711263C (en) | 2014-01-21 |
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| CA2711263A Expired - Fee Related CA2711263C (en) | 2008-02-08 | 2009-02-06 | Compositions and methods for the treatment of xerostomia |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US10471283B2 (en) |
| EP (1) | EP2249789A4 (en) |
| JP (1) | JP2011511793A (en) |
| CN (2) | CN101951877A (en) |
| AR (1) | AR070355A1 (en) |
| AU (1) | AU2009212321B2 (en) |
| BR (1) | BRPI0906462A2 (en) |
| CA (1) | CA2711263C (en) |
| MX (1) | MX2010005007A (en) |
| MY (1) | MY157782A (en) |
| RU (2) | RU2491928C1 (en) |
| TW (1) | TWI409084B (en) |
| WO (1) | WO2009100265A2 (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BR112013003722A2 (en) * | 2010-08-18 | 2016-08-02 | Colgate Palmolive Co | care products and methods of use and manufacture |
| US9717929B2 (en) | 2010-12-07 | 2017-08-01 | Colgate-Palmolive Company | Dentifrice compositions containing calcium silicate and a basic amino acid |
| SG190974A1 (en) * | 2010-12-23 | 2013-07-31 | Colgate Palmolive Co | Aqueous oral care composition comprising xanthan gum, cellulose gum and carbomer |
| CN102085369B (en) * | 2011-01-28 | 2012-07-04 | 武汉耦合医学科技有限责任公司 | Medical gel product for xerostomia and preparation method thereof |
| CA2905991C (en) | 2013-03-14 | 2023-03-14 | 3In1 Dental Pllc | Compositions for treatment of xerostomia and for tooth treatment |
| RU2538699C1 (en) * | 2013-11-29 | 2015-01-10 | Закрытое акционерное общество "ФИРН М" (ЗАО "ФИРН М") | Pharmaceutical composition for treating individuals suffering xerostomia |
| RU2554504C1 (en) * | 2014-02-20 | 2015-06-27 | Андрей Константинович Иорданишвили | Method of treating drug sialoadenopathy |
| CN104840958B (en) * | 2015-05-28 | 2018-03-30 | 广州帝奇医药技术有限公司 | Artificial transmucosal composition and its preparation method and application |
| JP2015221814A (en) * | 2015-07-10 | 2015-12-10 | コルゲート・パーモリブ・カンパニーＣｏｌｇａｔｅ−Ｐａｌｍｏｌｉｖｅ Ｃｏｍｐａｎｙ | Oral care product, and usage and manufacturing method of the same |
| CN105616205A (en) * | 2016-01-26 | 2016-06-01 | 浙江浙北药业有限公司 | White-strip composition |
Family Cites Families (85)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA696470A (en) * | 1962-02-15 | 1964-10-20 | The Procter & Gamble Company | Oral compositions for caries prophylaxis |
| US3538230A (en) | 1966-12-05 | 1970-11-03 | Lever Brothers Ltd | Oral compositions containing silica xerogels as cleaning and polishing agents |
| US3678154A (en) | 1968-07-01 | 1972-07-18 | Procter & Gamble | Oral compositions for calculus retardation |
| US3535421A (en) | 1968-07-11 | 1970-10-20 | Procter & Gamble | Oral compositions for calculus retardation |
| US4152418A (en) | 1970-04-01 | 1979-05-01 | Lever Brothers Company | Zinc and enzyme mouthwash and mouthwash concentrate for reducing dental plaque and calculus formation |
| US3696191A (en) | 1970-11-10 | 1972-10-03 | Monsanto Co | Dental creams containing enzymes |
| US3943241A (en) | 1971-08-30 | 1976-03-09 | General Mills, Inc. | Cariostatic composition |
| US3932608A (en) | 1971-08-30 | 1976-01-13 | General Mills, Inc. | Food composition |
| US4058595A (en) | 1971-10-13 | 1977-11-15 | Colgate-Palmolive Company | Stabilized toothpastes containing an enzyme |
| US3932605A (en) | 1972-06-12 | 1976-01-13 | Jaroslav Vit | Dental treatment |
| US3988434A (en) | 1972-08-07 | 1976-10-26 | Schole Murray L | Dental preparation |
| US3959458A (en) | 1973-02-09 | 1976-05-25 | The Procter & Gamble Company | Oral compositions for calculus retardation |
| US4025616A (en) | 1973-03-06 | 1977-05-24 | The Procter & Gamble Company | Oral compositions for plaque, caries and calculus retardation with reduced staining tendencies |
| US3937807A (en) | 1973-03-06 | 1976-02-10 | The Procter & Gamble Company | Oral compositions for plaque, caries, and calculus retardation with reduced staining tendencies |
| US3862307A (en) | 1973-04-09 | 1975-01-21 | Procter & Gamble | Dentifrices containing a cationic therapeutic agent and improved silica abrasive |
| US4100269A (en) | 1973-06-28 | 1978-07-11 | Lever Brothers Company | Anticalculus dentifrice |
| US4022880A (en) | 1973-09-26 | 1977-05-10 | Lever Brothers Company | Anticalculus composition |
| US3925543A (en) | 1973-11-01 | 1975-12-09 | Colgate Palmolive Co | Antibacterial oral compositions containing preservative-antioxidants |
| US3991177A (en) | 1973-11-27 | 1976-11-09 | Colgate-Palmolive Company | Oral compositions containing dextranase |
| US4011309A (en) | 1975-01-20 | 1977-03-08 | Marion Laboratories, Inc. | Dentifrice composition and method for desensitizing sensitive teeth |
| US4051234A (en) | 1975-06-06 | 1977-09-27 | The Procter & Gamble Company | Oral compositions for plaque, caries, and calculus retardation with reduced staining tendencies |
| US4064138A (en) | 1975-11-12 | 1977-12-20 | General Mills, Inc. | Amino acid derivatives |
| ZA773318B (en) | 1976-06-18 | 1978-04-26 | I Kleinberg | Means and method for improving natural defenses against caries |
| USRE31181E (en) | 1976-06-18 | 1983-03-15 | Means and method for improving natural defenses against caries | |
| US4042680A (en) | 1976-08-02 | 1977-08-16 | Indiana University Foundation | Anticariogenic maloaluminate complexes |
| US4108979A (en) | 1976-08-02 | 1978-08-22 | Indiana University Foundation | Dentifrice preparations comprising aluminum and a compatible abrasive |
| US4108981A (en) | 1976-08-02 | 1978-08-22 | Indiana University Foundation | Alkaline oral compositions comprising aluminum and a carboxylic acid |
| US4146607A (en) | 1977-11-07 | 1979-03-27 | Lever Brothers Company | Synergistic anti-plaque mixture with tetradecylamine plus aluminum and/or zinc |
| US4160821A (en) | 1978-02-27 | 1979-07-10 | Johnson & Johnson | Treatment for gingivitis |
| GB1573727A (en) | 1978-05-19 | 1980-08-28 | Colgate Palmolive Co | Dentifrices |
| US4216961A (en) | 1978-08-04 | 1980-08-12 | Mcquillan Mary J | Table baseball apparatus |
| US4225579A (en) | 1979-02-27 | 1980-09-30 | Israel Kleinberg | Means and method for improving defenses against caries |
| US4340583A (en) | 1979-05-23 | 1982-07-20 | J. M. Huber Corporation | High fluoride compatibility dentifrice abrasives and compositions |
| US4339432A (en) | 1979-06-20 | 1982-07-13 | Lever Brothers Company | Oral mouthwash containing zinc and glycine |
| US4269822A (en) | 1979-07-20 | 1981-05-26 | Laclede Professional Products, Inc. | Antiseptic dentifrice |
| JPS5846483B2 (en) | 1979-09-20 | 1983-10-17 | ライオン株式会社 | Oral composition |
| JPS5835965B2 (en) | 1979-07-31 | 1983-08-05 | ライオン株式会社 | Oral composition |
| US4355022A (en) | 1981-07-01 | 1982-10-19 | Interon, Inc. | Method of dental treatment |
| US4532124A (en) | 1981-08-19 | 1985-07-30 | Development Finance Corporation Of New Zealand | Dental rinse |
| JPS58118509A (en) | 1981-12-29 | 1983-07-14 | Lion Corp | Composition for oral cavity |
| US4885155A (en) | 1982-06-22 | 1989-12-05 | The Procter & Gamble Company | Anticalculus compositions using pyrophosphate salt |
| US4477429A (en) * | 1982-08-26 | 1984-10-16 | Johnson & Johnson Products, Inc. | Oral compositions comprising N.sup.α -alkyl derivatives of arginine |
| US4725576A (en) | 1983-12-29 | 1988-02-16 | Research Foundation Of State University Of New York | Fungicidal polypeptide compositions containing L-histidine and methods for use therefore |
| US4528181A (en) | 1984-02-01 | 1985-07-09 | Colgate-Palmolive Company | Dentifrice containing dual sources of fluoride |
| US5334617A (en) | 1984-03-19 | 1994-08-02 | The Rockefeller University | Amino acids useful as inhibitors of the advanced glycosylation of proteins |
| GB8411731D0 (en) | 1984-05-09 | 1984-06-13 | Unilever Plc | Oral compositions |
| US5000939A (en) | 1984-06-12 | 1991-03-19 | Colgate-Palmolive Company | Dentifrice containing stabilized enzyme |
| JPH0742219B2 (en) | 1984-07-26 | 1995-05-10 | ライオン株式会社 | Oral composition |
| US4538990A (en) | 1984-09-24 | 1985-09-03 | Medical College Of Ga. Research Institute, Inc. | Method of decreasing the permeability of a dental cavity |
| CH671879A5 (en) | 1987-02-26 | 1989-10-13 | Nestle Sa | |
| US4820506A (en) * | 1987-05-01 | 1989-04-11 | Research Foundation, State University Of New York | Salivary stimulant |
| US4866161A (en) | 1987-08-24 | 1989-09-12 | University Of South Alabama | Inhibition of tartar deposition by polyanionic/hydrophobic peptides and derivatives thereof which have a clustered block copolymer structure |
| US5004597A (en) | 1987-09-14 | 1991-04-02 | The Procter & Gamble Company | Oral compositions comprising stannous flouride and stannous gluconate |
| GB8729564D0 (en) | 1987-12-18 | 1988-02-03 | Unilever Plc | Oral compositions |
| US4842847A (en) | 1987-12-21 | 1989-06-27 | The B. F. Goodrich Company | Dental calculus inhibiting compositions |
| US5438076A (en) | 1988-05-03 | 1995-08-01 | Perio Products, Ltd. | Liquid polymer composition, and method of use |
| US5096700A (en) | 1990-09-28 | 1992-03-17 | The Procter & Gamble Company | Halogenated aminohexanoates and aminobutyrates antimicrobial agents |
| US5370865A (en) | 1992-05-15 | 1994-12-06 | Kao Corporation | Composition for use in oral cavity |
| US5286480A (en) | 1992-06-29 | 1994-02-15 | The Procter & Gamble Company | Use of N-acetylated amino acid complexes in oral care compositions |
| US5496558A (en) * | 1993-03-02 | 1996-03-05 | Block Drug Company Inc. | Solid form xerostomia product |
| EP0704533A1 (en) | 1994-09-30 | 1996-04-03 | Bayer Ag | An attenuated vaccination virus, a method to make the virus and a pharmaceutical compositions comprising the virus |
| DE69618786T2 (en) | 1995-07-10 | 2002-11-07 | Unilever Nv | HEAT GENERATING TOOTHPASTE |
| JPH0958053A (en) | 1995-08-29 | 1997-03-04 | Ricoh Co Ltd | Image forming apparatus |
| CA2184802C (en) | 1995-10-10 | 2007-07-31 | Karl-Heinz Bender | Process for manufacture of imidazo benzodiazepine derivatives |
| CN1093756C (en) | 1996-01-31 | 2002-11-06 | 尤尼利弗公司 | Oral preparations |
| US5762911A (en) * | 1996-03-05 | 1998-06-09 | The Research Foundation Of State University Of New York | Anti-caries oral compositions |
| US6488961B1 (en) | 1996-09-20 | 2002-12-03 | Ethypharm, Inc. | Effervescent granules and methods for their preparation |
| US5906811A (en) | 1997-06-27 | 1999-05-25 | Thione International, Inc. | Intra-oral antioxidant preparations |
| US5922346A (en) | 1997-12-01 | 1999-07-13 | Thione International, Inc. | Antioxidant preparation |
| US6805883B2 (en) | 1998-03-12 | 2004-10-19 | Mars, Incorporated | Food products containing polyphenol(s) and L-arginine to stimulate nitric oxide |
| US5997301A (en) | 1998-10-20 | 1999-12-07 | Linden; Lars Ake | Treatment of tooth surfaces and substances therefor |
| US6436370B1 (en) | 1999-06-23 | 2002-08-20 | The Research Foundation Of State University Of New York | Dental anti-hypersensitivity composition and method |
| GB2354441A (en) * | 1999-08-06 | 2001-03-28 | Mccormack Ltd | Composition for treating dentine hypersensitivity |
| WO2001076549A2 (en) | 2000-04-11 | 2001-10-18 | Gerald Mc Laughlin | Composition and method for whitening teeth |
| US8283135B2 (en) * | 2000-06-30 | 2012-10-09 | The Procter & Gamble Company | Oral care compositions containing combinations of anti-bacterial and host-response modulating agents |
| US20020081360A1 (en) | 2000-12-27 | 2002-06-27 | Andreas Burgard | Salts of L-amino acid having improved taste and their preparation |
| IL165910A0 (en) | 2002-07-03 | 2006-01-15 | Pericor Science Inc | Compositions of hyaluronic acid and methods of use |
| US20050215473A1 (en) * | 2003-05-09 | 2005-09-29 | Enrique Alvarez | Prophylactic and therapeutic uses of FGF-20 in radiation protection |
| JP2007536382A (en) | 2004-05-10 | 2007-12-13 | キュラジェン コーポレイション | Prophylactic and therapeutic use of FGF-20 in radiation protection |
| PT1793799E (en) * | 2004-08-02 | 2010-07-29 | Glaxosmithkline Consumer Healt | Novel composition for treating xerostomia |
| KR101153242B1 (en) | 2004-09-17 | 2012-06-08 | 아지노모토 가부시키가이샤 | Agent and food for preventing/improving functional digestive disorder |
| MX348545B (en) | 2005-07-12 | 2017-06-16 | Colgate-Palmolive Company * | Oral care implement having reservoir for dispensing active agent. |
| CN101478982A (en) | 2006-03-17 | 2009-07-08 | 康达医药科技有限公司 | Method and composition for protection against radiation |
| US8501161B2 (en) | 2006-05-09 | 2013-08-06 | Colgate-Palmolive Company | Oral care regimen |
| AR072341A1 (en) | 2008-02-08 | 2010-08-25 | Colgate Palmolive Co | METHODS FOR THE PRODUCTION OF ARGININE BICARBONATE |
-
2009
- 2009-02-06 WO PCT/US2009/033291 patent/WO2009100265A2/en active Application Filing
- 2009-02-06 CA CA2711263A patent/CA2711263C/en not_active Expired - Fee Related
- 2009-02-06 TW TW098103771A patent/TWI409084B/en not_active IP Right Cessation
- 2009-02-06 MX MX2010005007A patent/MX2010005007A/en active IP Right Grant
- 2009-02-06 JP JP2010546016A patent/JP2011511793A/en active Pending
- 2009-02-06 RU RU2012112933/15A patent/RU2491928C1/en not_active IP Right Cessation
- 2009-02-06 CN CN2009801048912A patent/CN101951877A/en active Pending
- 2009-02-06 EP EP20090707366 patent/EP2249789A4/en not_active Ceased
- 2009-02-06 AR ARP090100427A patent/AR070355A1/en unknown
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| CN104398396A (en) | 2015-03-11 |
| RU2491928C1 (en) | 2013-09-10 |
| WO2009100265A2 (en) | 2009-08-13 |
| CA2711263C (en) | 2014-01-21 |
| TW200946135A (en) | 2009-11-16 |
| CN101951877A (en) | 2011-01-19 |
| BRPI0906462A2 (en) | 2015-07-14 |
| MY157782A (en) | 2016-07-29 |
| US20110189110A1 (en) | 2011-08-04 |
| TWI409084B (en) | 2013-09-21 |
| AU2009212321B2 (en) | 2012-04-19 |
| EP2249789A4 (en) | 2014-01-15 |
| RU2455001C2 (en) | 2012-07-10 |
| WO2009100265A3 (en) | 2009-11-05 |
| JP2011511793A (en) | 2011-04-14 |
| RU2010137342A (en) | 2012-03-20 |
| EP2249789A2 (en) | 2010-11-17 |
| US10471283B2 (en) | 2019-11-12 |
| AR070355A1 (en) | 2010-03-31 |
| AU2009212321A1 (en) | 2009-08-13 |
| MX2010005007A (en) | 2010-05-27 |
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