CA2378587A1 - Stable hydrogenated lupulone antibacterial oral compositions - Google Patents

Stable hydrogenated lupulone antibacterial oral compositions Download PDF

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Publication number
CA2378587A1
CA2378587A1 CA002378587A CA2378587A CA2378587A1 CA 2378587 A1 CA2378587 A1 CA 2378587A1 CA 002378587 A CA002378587 A CA 002378587A CA 2378587 A CA2378587 A CA 2378587A CA 2378587 A1 CA2378587 A1 CA 2378587A1
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Prior art keywords
oral composition
weight
dentifrice
hydrogenated lupulone
present
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
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CA002378587A
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French (fr)
Inventor
Prem K. Sreenivasan
Nuran Nabi
Abdul Gaffar
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Colgate Palmolive Co
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Individual
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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61QSPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00Cosmetics or similar toiletry preparations
    • A61K8/18Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34Alcohols
    • A61K8/347Phenols
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents

Abstract

A stable antibacterial oral composition containing a hydrogenated lupulone a nd an anionic surfactant.

Description

STABLE HYDROGENATED LUPULONE
ANTIBACTERIAL ORAL COMPOSITIONS
BACKGROUND OF THE INVENTION
1. Field of the Invention This invention relates to a stable oral composition containing an effective antibacterial amount of a hydrogenated lupulone derived from beer hops.
2. The Prior Art It is difficult to predict the efficacy of antibacterial agents when incorporated in any delivery vehicle and particularly in oral compositions. For example, dental plaque is a soft deposit which forms on teeth as opposed to calculus which is a hard calcified deposit on teeth.
Unlike calculus, plaque may form on any part of the tooth surface, particularly at the gingival margin and is implicated in the occurrence of gingivitis. Cationic antibacterial compounds such as chlorhexidine, benzthonium chloride and cetyl pyridinium chloride have been used by the art as antibacterial antiplaque agents in oral compositions. However, such agents are generally not effective when there is also present in the oral composition an anionic surfactant required for the effective performance of oral compositions such as toothpaste and mouthrinses.
Beta-acids, also known as lupulones, derived from beer hops, are known to the art to exhibit antibacterial action in oral compositions. For example, US 3,932,603 discloses that hop extract resins, such as lupulone and humulone, are effective as antimicrobials against cariogenic streptococci. US 5,370,863 discloses oral compositions containing hop acids such as tetrahydroisohumulone which inhibit gram positive bacteria and plaque formation and periodontal disease.

15=10-2001 ' 15 X1.,15,'.,58 FR ATE PATENT DEPT 732 87B ?853 TO
901145~F3923994455 P.05~ US0020967 Lupulones are also known to inhibit the growth of food-pathvge~.~; such as ListGria monoaytogenes (LTS Pedant Nvs. 5,286,506; 5,455,038). ~In~alditivn, the.l~ydmgemated-fvan; ' ' hexahydrolupulone, inhibits the growth of certain Lactobacilli (US PatGn~t~
No. 5,082,975. ~ ' ' Hydrogenated lupulones appoar to be more active end ~stable.than~ their na~n hy~roge~atod- :. . . ' . . . . -parant compounds. For example, hexahydrocolupulvae iti beliavad~~to-be ~ore~antibactarial; r ~ .. . _ - - w active than colupulone while hexahydrolupulone has bees found to:be'aic~'ra stabla.thtin~ ~ - . ~ . . . . . .. .
lupulone. Hexahydrocolupulone can be made by the chemical hydrogenation of evlupulane ~ - ' ' using a number of methods known in the at~t. For exaiaiplc, hydrogenation can be achieved=- . - -with platinum (I~ oude as a catalyst as descnbed byWiedl~(Be~r:=89:186:3 ~(195f~or.by . : . - . - . . , , .
Carson (1. Am. Chain. Soc. 73:1850 (1951). A method~fo~lirepa:il~g hacahydivlupulone re .~ ~ --_ -described in TJS Patent No. 5,082,975. .~: :.. : _ . ~ . . . . ... ~, , . .. .
~ . ' . - . - -:=
As will haeinafte: bo demonstrated, a disadvantage to the rise-o~
hydivga~atetl: . . '_ . _ .. . . : . . . .
lupulones in oral compositions such as dentifrice:, is that the~fupulono~ not-stab~e'aadw~.. . ..-..:
. _ - .. ~SOP~eS.into soluble and insoluble comp~n~ts on sto~ge;-this-.laek~vfal~ability:diseoiuagihg'.: . - -: :.
cvnunercial accaptaaca by consumer.:. - ~-~ -~ ' - =~.~=y"' : t ... . _. .. r . _ . . ; . . . ....: :v -: . _ , .
In acxordance with the present invention there is pro'rided~a stable'o~ail compciaition-: - . _ . .' . ' containing a hydrogenated lupulvne which compositioa.~is piepai~-by=achuixing (T)-a'~ ~- . . . . .- . , , -, .' solution of the hydrogenated lupulone in a flavor oil aiii'(-an-aliphatic.alcolzol~ such as. ethanol = ' . -with (2) humectant solution cvntainiag an anionic surfsctaiit'and'adji~st~;
~h~ gH~to.a-reago - . - . ' : . . ' .
of about 8.0 to about 10.5 to prepare a premix sad than adding ~t'tie pre0iix to the other - ~ , . . -. . . . . -: ... . . -ingredients of the oxal composition. .. - . __ . _~ :- ~ . . : . . . . _ . , The presence, in the hydrogenated lupulvna containing oral composition, of as anionic pvlycarboxylate polymer such as a maleie anhydridelmethyl vinyl, ether copolymer, as will hazinafter be demonstrated, materially enhances the antibacterial ~~roperties of the oral composition, AMENDED SHEET
r _ r . . ~r »n innn~ nt . ~n C~.t __ ~O~ O fYG

15-10-2001 15 c~6D1-15' 58 FR COLGRTE PHTENT DEPT ?32 8'~'B 7853 TO
90114'389239544fi5 P. 66~'' . CA 02378587 2002-O1-31 US0020967 PCT/US 00lZ0967 The tens "hydrogenated hipulone" as used herein;, includes within its:mea~aing hydrogenated lupulones including hexahydrolupulvne and heitahydmcoletpulone and mixtures ' ~ _ ~ _ which are prefe~d. in the practice of the present invention. ..' ' . - _. . .
. . . . . . . ~ . ~ . . ..
The hydrogenated lupulone used to prepare oral compositioa:~~ ofWe p=esent.inveatian ' ~ .' ~ . .
such as dentifricea, ,gels and mouthrinses is incorporated in tha oral cbmposition-iti an w . ' effective aatiplaque amount, typically in a range of attbut~0:003to $bout~a%,~pieferatily about.: . ... . ~ . . :' 0.02 to about 1 % by weight. A mixtut>: of hydmgenat6d_lupulvnes vamei ly v .
. . . _ ~: .. ~ . . . : ..' . . _. .
hexahydrolupuloae (35% by weight) and hexahydrocohipulbae (65%:by ~ciieight)~is~avanlab'le ~ - _. _ . . .':=ro :.
commercially fmmHaas Hop Products, Washi~ogton,-Z?.C - ~=~-.:-~:-:..:.- :_y...
_ _ _ . , _ ..... ~, : :-~...w . _.:.:-When the oral composition is a gel yr paste, such compositiowis F~npared using an '-orally acceptable vehicle, including a water phase with-'hut<iectaxtt ~liich'is :preferably-'.: .. - :: . ._.. . .
81YC~~ sorbitol, an allsylene glycol or.mixt<uses.thacof'.'v~riierein'~rafer-~is~piesent~typicaDy"': . . .
. . ~ , ~ ._ : ' in an amount of about 15 to about 40% by weight_and~glyCeride; soiliitol aadloF tliralkyt'ene'_~_ .- - ..
glycol humectant typically total about 20 to about 75°%~'.by v~oight:o~'th~~a~ial-compvsitioh; . .. _ .. _ . : ~.:~ ._: ~:-:
more typically about 25 t0 about 60% by weight. :' .' . . ~ _ . : ... ._. . .
_ _. .,. . . , . ; _ . .-_ The vehicle of the~oral paste or gel compositiost may aLw'~contain:a~ deatally ~ . ' ' - . :..: . . .
acceptable abrasive material such as sodium bica~aoatv,.scdium metaphcisphata;
pvteaaium ..~ .:.~ :: ~._..:.:. -Y: .
metaphosphate, tricalcium phosphate, dihydrated dicalciura ph~s~l~te~ ~r-.~h~d=ous.di~calciuui. '.~.- ~~ .. _ ~ . ;,:-,-' phosphate, calcium pyrophosphate, calcium carbonate;~alieminum~silicate;~
hydrated alumna, .:. . .._ ,: :~.~,=.:
calcined aluzaina, silica, bentonite, and mixtures there 'af~ .'The abFasive rniterial is generally .. . . . . .
present in the paste yr gel composition is weight cvnocirttatiens of about 't 0% to about 60% . ~ ' ' . ' ' . .
by weight, preferably about 10% to about 30% is a gel and about 25% to about 60% in a .
paste.
AMENDED SHEET
c_..t _,.:i~t~~lfll~lmt 91~Af1 Fmof nr 'Rq'~ P fTTi Toothpastes as well as gel dentifrices typically contain a natural or synthetic thickener or gelling agent in proportions of about 0.1 to about 10% by weight, preferably about 0.5 to about 5% by weight. Suitable thickeners or gelling agents include Irish moss, iota-carrageenan, kappa-carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethyl propyl cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose and silica thickeners such as Sylodent 15..
In the embodiment of the present invention wherein the oral composition is substantially liquid in character such as a mouthwash or rinse, the vehicle is typically a water-alcohol mixture. Generally, the weight ratio of water to alcohol is in the range of from about 3:1 to 10:1 and preferably about 4:1 to about 6:1. The alcohol is a non-toxic alcohol such as ethanol or isopropanol. A humectant such as glycerin, sorbitol or an alkylene glycol or mixtures thereof, may be present in amount of about 10 to about 40% by weight.
Mouthrinses typically contain about 50 to about 85% of water, about 0 to 20% by weight of a non-toxic alcohol and about 10 to about 40% by weight of the humectant .
Anionic surfactants are used in the oral compositions of the present invention to achieve increased prophylactic action and foaming. Unexpectedly, the presence of the anionic surfactant also plays a role in the stabilization of the hydrogenated lupulone. Suitable examples of anionic surfactants useful in the practice of the present invention include water soluble salts of higher fatty acid monoglyceride monosulfates, such as the sodium salt of the monosulfated monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher fatty acid esters of 1,2- dihydroxy propane sulfonate, and the substantially saturated higher aliphatic acyl amides of lower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals and alkoyl taurines, and the like. Examples of the last mentioned amides and taurates are N-lauroyl sarcosine, and the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material as well as N-methyl-N-cocoyl (or oleoyl or palmitoyl) taurines.
The anionic surfactant is present in the oral compositions of the present invention in an amount effective to stabilize the hydrogenated lupulone, which amount ranges from about 0.25 to about 3.0% by weight and preferably about 0.5 to about 2.0% by weight.
When surfactants other than anionic surfactants are used in hydrogenated lupulone containing oral compositions, the hydrogenated lupulone on storage is observed to be unstable.
Other agents which may be included in the oral composition of the present invention are fluoride salts to provide an anticaries effect, as for example, sodium fluoride, potassium fluoride, sodium monofluorophosphate and sodium hexafluorosilicate. The fluoride-ion providing salt is generally present in the oral composition at a concentration of about 0.0005 to about 3.0% by weight. Any suitable minimum amount of such salt may be used, but it is preferable to employ sufficient fluoride salt to release about 300 to ?,000 ppm, more preferably about 800 to about 1,500 ppm, of fluoride ion.
Antitartar agents such as sodium tripolyphosphate, tetrapotassium or tetrasodium pyrophosphate, or mixtures thereof, may be present in the oral compositions of the present invention at concentrations from about 0.5 to about 8% by weight.
Agents used to diminish teeth sensitivity such as potassium chloride, potassium nitrate and potassium citrate may also be included in oral compositions of the present invention at concentrations of about 0.1 to about 10% by weight.
Various other materials may be incorporated in oral compositions of this invention including preservatives, such as sodium benzoate, peroxide whitening compounds vitamins and chlorophyll compounds. These adjuvants, when present, are incorporated in the compositions in amounts which do not substantially adversely affect the properties and characteristics desired.
Flavoring oils useful in the practice of the present invention to dissolve the hydrogenated lupulone and to impart palatability to the oral composition include oil of spearmint, peppermint, wintergreen, sassafras, clove, sage, eucalyptus, cinnamon, lemon, and orange, and methyl salicylate.
Sweetening agents may also be present and include sucrose, lactose, maltose, xylitol, sodium cyclamate, perillartine, aspartyl phenyl alanine methyl ester and saccharine.

Suitably the flavor oil and sweetening agent each comprise from about 0.1% to 2% of the oral composition.
Antibacterial agents in addition to the hydrogenated lupulone may be included in the oral composition of the present invention and particularly noncationic halogenated diphenyl ethers agents which are desirable from considerations of effectiveness and safety such as 2',4,4' trichloro-2 hydroxy-diphenyl ether (Triclosan) and 2,2'-dihydroxy-5,5' dibromophenyl ether. The antibacterial agent, when present in the oral composition is present in concentrations of about 0.05 to about 2% by weight and preferably 0.1 to about 1% by weight.
Anionic polycarboxylate polymers having a molecular weight of about 1,000 to about 5,000,000, preferably about 30,000 to about 500,000 in the form of their free acids or preferably partially or more preferably fully neutralized water soluble alkali metal (e.g.
potassium and preferably sodium) or ammonium salts are included in the hydrogenated lupulone containing oral composition of the present invention to enhance the antibacterial efficacy of the hydrogenated lupulone. Preferred anionic polycarboxylate polymers are 1:4 to 4:1 copolymers of malefic anhydride or acid with another polymerizable ethylenically unsaturated monomer, preferably methyl vinyl ether/maleic anhydride having a molecular weight (M.W.) of about 30,000 to about 1,000,000, most preferably about 30,000 to about 500,000. These copolymers are available, for example, under the trade designation Gantrez AN 139 (M.W. 500,000), AN 119 (M.W. 250,000); and preferably Gantrez S-97 Pharmaceutical Grade (M.W. 70,000), of GAF Corporation.' Other polycarboxylate polymers useful in the practice of the present invention are carboxyvinyl polymers commercially available, for example, under the trade designation Carbopol 934,940 and 941 from B.F. Goodrich, these polymers being comprised of a colloidally water-soluble polymer of polyacrylic acid crosslinked with from about 0.75% to about 2.0% of polyalkyl sucrose or polyalkyl pentaerythritol often with molecular weights of 4 to 5 million or more.
The anionic polycarboxylate polymer when employed in the oral composition of the present invention is incorporated in the composition in amounts of about 0.05 to about 5%, preferably about 0.1 to about 3% by weight.
15-10-2001 ~ 15 2001 15:56 FR COLGNTE PRTENT DEPT ?3~ 8i9 ~r853 TO
901145~B92j~94465 P.Oi~ US0020967 ?o prepare the oral composition of the present invention a premiJC solution of the . ' ~ ' hydrogenated lupulone is prepared separately, wherein.sin aqueous solnticm containing ab'vut .-2 to about 2.5% by weight of the anionic surfactant, preferably warmed to a temperature of . . .. -.
60 to 80°C, is admixed with an aqueous $ol~ivn containing about. IO..tv about 15% by weight '." . .
of one or more huntectants such ss ,glycerin, sorbitol arSpioPYlene glycol add-then.ad~ni~ced' : . . . '.
with a solution of hydrogenated lupulone in a~mixture~of flavor oil~and~al~;oliol~to provide ~a : ~ ' ' combined solution confaining the hydrogenated lupulone=in amounts ~of about 0.03. to about ~ ' ' ' 0.3% by weight, the flavor oil in amounts of about 0.f5'tv~~aboirt 1°i~
by~woight'aiiii au- .: ".:'. ' .. ..'.
aliphatic alcohol such as ethanol yr isapropattol in an~suio~uit-o~~about~l~5~~ta.aboiit 25%:by'. ' ~ . ' weight Upon completion of admixing, the pH of the adin;xod eoliitivris:ius~aiijusted trb'a pH of ' . ' about 8 to about 10.5, preferably about 8.5 to about 9i:.: . '.. . ..~ . - ' .
. . . - . . .. . : .. '.-The oral compositions of the present invention nlay be pt~par~d~b~r~suitably muai~g. _. .. . _ ., . . .
the hydrogenated lupulone premix solution, prcpared:as'previously described;
vvith~the~vtliei ' . . '. ' .
r . ~~ of ~e .oral composition. For exmnplo, iu~the:greparation of a':mouthriase; the :' ... . .:.:_.~:: : : . _ -: premix of hydrogenated lupulone dispersed in the vf~
alcoliol;!>fimoectant,= sit; - - . .-.._.. .. . . ... ~ . t ' .1 : . '., Vi aml flavor is added to sa aqueous solution of any additional ingredients .to..be:pcesv~it~in-tfie:.~~. ..
mouthrisne and mixed under vacuum for about 15-30'vtinutes_ '?'he iresul>ring t~inse~prvduct is' -.
then packaged. Dentifrices are prepared similarly, additivnai cttick~ec aad:polishiiig $gents : . - ' _ .. .
., being included in the last or penultimate step. . . ... _ . . . . ' _ ~ ..: ~ -, ,.. . ' . _ The following Fxau~ples further illus~ate the present invantion;'but it.is uiidecstood'.. . .. . .. : _ . .
that the invention is not limited thereto. All arnouats baud prvporti'ons'refe~crod'td he~eia=~d . : . _ ..... . .. . .
in tho appended claims are by weight unless othetwi5e''indicsted: ~ .. ' , , .
. , _. ... . . . ~ . - . ' A moutlu'inse containing a mixtsuz of hydrogenated lupulones, namely, hexahydmlupulone (35% by weight) and hexahydrocolupulvae (65% by ~~aight), the n~ixhue ' ' hereinafter being refeaed to ss "fiHBA" was prepared. The ingredients of the mouttuinse are listed in Table,I below. For the purpose of comparison, a hydrogenated lu~~ulone containing a mouthrinst was prepared having tire composition disclosed in US 5,370,86~3, the ingredients of which are listed iun~Table II below.
AMENDED SHEET
r_..i __:~~~cmnmm~ ~~~en C..,.,t ..,. ~5~0~ D M-1 TABLE I
Insredient % by Wei ht HHBA 0.03 Ethanol 15.0 Glycerin 10.0 Sodium lauryl sulfate0.75 Sorbitol 10.0 Propylene glycol 15.0 Flavor oil 0.1 KOH (10%) 0.2 KH2P04 (25%) 0.1 Distilled water cF 100.00 s. ad.

The HHBA premix used to prepare the mouthrinse was prepared as follows:
Stage I: The anionic surfactant sodium lauryl sulfate, was dissolved in warm (60-70°C) water.
Stage H: A separate solution of HHBA dissolved in flavor oil, followed by the addition of ethanol, was prepared.
Stage III: A separate solution of sorbitol, propylene glycol and glycerin was prepared.
The solutions prepared in Stages I and III were admixed followed by admixing with the solution of Stage H. The pH of the combined solutions were adjusted to 7.0 with 10% KOH
followed by further adjustment of the pH to 9.0 with 25% K2HP04 to prepare the HHBA
premix. The premix was then added to the remainder of the mouthrinse ingredients to prepare the mouthrinse of Table I.
The comparative mouthrinse of Table II was prepared as follows:
Stage I: Sodium saccharin and Pluronic F127 surfactant were dissolved in warm (60-70°C) water. Next glycerol was added and mixed. Pluronic F127 surfactant is a polyoxyethylene/polyoxypropylene block copolymer nonionic surfactant available from BASF Corporation, Parsippany, New Jersey 07064.
Stage II: I~A was dissolved in flavor oil.
Stage III: A separate solution of ethanol and benzoic acid was prepared.
The solutions prepared in Stages I and III were admixed with the solution in Stage II.
Thereafter the color and sodium hydroxide were added.
TABLE II
In redient % by Wei ht Tetrahydroisohumulone 0.0025 Ethanol 16.25 Glycerin 10.0 Pluronic F127 0.12 Benzoic acid 0.05 Sodium saccharin 0.05 Flavor oil 0.1~

Color 0.04 Sodium hydroxide (10% 0.15 sol.) Distilled water .s. 100.00 ad.

Stability Test After being stored in sealed glass jars for 3 days at 22°C, the mouthrinse of Table I
remained a clear, homogeneous solution, whereas the comparative mouthrinse of Table II when subjected to the same aging conditions, separation of the IAA into soluble and insoluble components was observed.

Example II
There is provided in Table III below the ingredients of a stable Fi>-~A
dentifrice containing a dicalcium phosphate abrasive prepared in the manner previously described.
TABLE III
In redient % by W ei ht Glycerin 10.0 Carageenan gum 0.8 Sorbitol (70%) 16.0 HI-iBA 0.2 Sodium saccharin 0.2 Sodium fluoride 0.25 Dicalcium phosphate 48.0 dihydrate Sodium lauryl sulfate 2.0 Flavor oil 1.0 Polyethylene glycol 1.0 Sodium monofluorophosphate0.76 Tetrasodium pyrophosphate0.25 Example III
There is provided in Table IV below, the ingredients of a stable ~A dentifrice containing dicalcium phosphate and precipitated calcium carbonate abrasives prepared in the manner previously described.
TABLE IV
In redient % by Wei ht Glycerin 15.0 Carageenan gum 0.65 Sorbitol (70%) 10.0 1~ A 0.3 Sodium Saccharin 0.15 Sodium Fluoride 0.25 Precipitated calcium 36.0 carbonate Dicalcium phosphate 13.0 Sodium lauryl sulfate 2.3 Flavor oil 0.95 Water .s. 100.00 Example IV
The mouthrinse of Table I was tested using a microbiological assay, namely, Minimum Inhibitory Concentration (MIC) and bacterial growth inhibition on hydroxyapatite discs. The gram-positive oral bacterium Actinomyces viscosus was routinely grown overnight in trypticase soy broth (Difco Labs, Detroit, MI) at 37°C. A gram strain of the cultures was prepared to determine the purity of the cultures prior to in vitro testing of the mouthrinse.
MIC ASSAY
The bacterial strain grown for 18 hours at 37°C in trypticase soy broth (TSB) was diluted in fresh broth to adjust its optical density between 0.1 and 0.2 absorption units at 610 nm prior to MIC determinations.

The mouthrinse of Table I and a placebo mouthrinse were diluted in TSB and the MIC
was determined using the microtiter format according to standard procedures (Manual of Clinical Microbiology, 1995). The placebo mouthrinse was prepared in the same manner as the mouthrinse of Table I except HI~BA was not included in the mouthrinse. The MIC
results are recorded in Table V below.
Bacterial Growth Inhibition Assav on Ilvdroxvanatite Disks The antiplaque effect of the mouth rinse of Table I and the placebo rinse described above were assessed by a growth inhibition test with A. viscosus using hydroxyapatite disks treated with the rinse and bacterial growth was monitored by measuring optical density (OD) at 610 nm after 2 hours and 24 hours after treatment of the disks. In this test, the hydroxyapatite disk was placed in a test tube containing clarified human saliva and incubated overnight at 37°C. Thereafter, the saliva was removed from the tube and replaced with mouthrinse solution and incubated for 30 minutes at 37°C whereupon the disk was placed in a transparent plastic tube containing bacterial strains diluted in TSB to an OD of 0.25 at 610 nm.
The results of the microbiological assays are recorded in Table VI below.
TABLE V
MIC as a function of % rinse MIC as a function of active Composition concentration for bacterial inhibition concentration (in ppm) Table I Rinse 0.39 2.3 Placebo Rinse 1.56 --The results in Table V indicate that the ~A mouthrinse of Table I was active against A.
viscosus and provided better antibacterial efficacy than the placebo rinse.
TABLE VI
Composition Bacterial OD at 2 hrs. Bacterial OD at 24 hrs.
Table I Rinse 0.3 0.5 Placebo Rinse 0.52 1.35 The results recorded in Table VI indicate that treatment with the mouthrinse of Table I resulted in fewer bacteria as determined by lower bacterial OD as compared to the placebo rinse.

Antibacterial efficacy of dentifrices ~ Zone of Bacterial Inhibition with dentifrices:
The antibacterial efficacy of the dentifrice of Table IV and a placebo dentifrice were assessed by a zone of bacterial inhibition test with A. viscosus. The placebo dentifrice was prepared in the same manner as the dentifrice of Table IV except )SBA was not included in the dentifrice.
In this test, hydroxyapatite disks were treated with a IiI~BA containing dentifrice or the placebo and placed on an agar plate containing A. viscosus. The inhibition of bacterial growth around each disk zone was measured after 48 hours of incubation and the results are shown in Table VII below.
TABLE VII
Zone of inhibition in centimeters Table IV dentifrice 2.17 Placebo dentifrice 1.77 The results recorded in Table VII indicate that the Table IV dentifrice had a higher zone of inhibition than the placebo dentifrice indicating antibacterial efficacy.
~ Bacterial Growth Inhibition on hydroxyapatite The antibacterial effects of the Table IV dentifrice was assessed by a growth inhibition test with A. viscosus. The placebo dentifrice was prepared in the same manner as the dentifrice of Table IV except HI3BA was not included in the dentifrice. In this test, hydroxyapatite disks were treated with the dentifrice and bacterial growth monitored by measuring optical density at 610 nm after 24 hours post-treatment. The results are shown in Table VIII
below.
TABLE VIII
Bacterial Optical Density at 610 nm 24 hours post-treatment Table IV dentifrice 0.43 Placebo dentifrice 0.91 The results recorded in Table VIII indicate the highest optical density (a measure of bacterial growth) was observed with the placebo dentifrice, and a lower optical density from disks treated with the Table IV dentifrice indicating that the I~A containing dentifrice provided antibacterial efficacy.
S
Example IV
There is provided in Table IX below, the ingredients of a stable I~A
dentifrice containing an anionic polycarboxylate polymer, Gantrez S-97.
TABLE IX
%bvW
Silica abrasive 20.0 Sylodent 15 1.5 Glycerin 20.0 Iota carageenan 0.4 Sorbitol (70%) 20.85 I~iBA 0.3 Sodium saccharin 0.3 Sodium fluoride 0.243 Sodium lauryl sulfate 1.5 Flavor 1.0 Propylene glycol 0.5 Titanium dioxide 0.5 Gantrez S-97 2.0 I Sodium carboxymethyl 1.1 cellulose II Water q.s.

The antibacterial efficacies of the dentifrice of Table IX (Dentifrice Table IX) and a dentifrice identical to the dentifrice of Table IX except that Gantrez S-97 was absent from the dentifrice (Dentifrice C) were determined by examining the ability of each dentifrice to inhibit the growth of bacteria. For this test, a slurry of each dentifrice was prepared in water. The slurries were centrifuged and the resulting supernatant used to treat saliva coated hydroxyapatite disks for 30 minutes. The dentifrice treated hydroxyapatite disks were washed with water and incubated with a culture of Actinomyces viscosus. The growth of the culture was determined 24hours after incubation with the dentifrice treated disks. The results from triplicate samples are shown in Table X below and indicate bacterial growth as determined by measuring the optical density of each culture at 610 nm. Water treated disks were used as a control.
TABLE X
Treatment Bacterial Optical Density at 610 nm Dentifrice Table IX 0.50 Dentifrice C 0.61 Control 1.49 The results recorded in Table X indicate that although the dentifrice containing 0.3% by weight I~iBA (Dentifrice C) inhibits the growth of bacteria as evidenced by the lower bacterial optical density, the dentifrice containing I~iBA and Gantrez (Dentifrice Table IX) is more effective in inhibiting bacterial growth.

Claims (15)

What is claimed is:
1. A method for preparing a stable antibacterial oral composition containing a hydrogenated lupulone, the method comprising preparing a premix by admixing (1) a solution of the hydrogenated lupulone in a mixture of flavor oil and adjusting alcohol with (2) a humectant solution containing an anionic surfactant adjusting the pH of the combined solutions to a range of 8.0 to 10.5 and then adding the premix to the other ingredients of the oral composition.
2. The method of claim 1 wherein the hydrogenated lupulone is present in the composition in an amount in the range of about 0.003 to about 2.0% by weight.
3. The method of claim 1 wherein the hydrogenated lupulone is hexahydrolupulone.
4. The method of claim 1 wherein the hydrogenated lupulone is hexahydrocolupulone.
5. The method of claim 1 wherein the hydrogenated lupulone is a mixture of hexahydrocolupulone end hexahydrolupulone.
6. The method of claim 1 wherein the anionic surfactant is sodium lauryl sulfate.
7. The method of claim 1 wherein the anionic surfactant is present in the composition in an amount effective to stabilize the hydrogenated lupulone.
8. The method of claim 1 wherein the anionic surfactant is present in the oral composition in an amount ranging from about 0.25 to about 3.0% by weight.
9. The method of claim 1 wherein an anionic polycarboxylate polymer is present is the oral composition in an amount of about 0.05 to about 5.0% by weight.
10. A stable oral composition, prepared by the method of claim 1.
11. A stable antibacterial oral composition comprising about 0.003 to about 2%
by weight of a hydrogenated lupulone and about 0.25 to 3.0% by weight of an anionic surfactant.
12. The oral composition of claim 11 in which an anionic polycarboxylate polymer is present in an amount of about 0.05 to about 5.0% by weight.
13. The oral composition of claim 12 wherein the anionic polycarboxylate polymer is a copolymer of maleic anhydride and methyl vinyl ether.
14. The oral composition of claim 11 which is a toothpaste.
15. The oral composition of claim 11 which is a mouthrinse.
CA002378587A 1999-08-04 2000-08-01 Stable hydrogenated lupulone antibacterial oral compositions Abandoned CA2378587A1 (en)

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