NO171094B - PROCEDURE FOR PREPARING AN ORAL CARE PREPARATION - Google Patents
PROCEDURE FOR PREPARING AN ORAL CARE PREPARATION Download PDFInfo
- Publication number
- NO171094B NO171094B NO834201A NO834201A NO171094B NO 171094 B NO171094 B NO 171094B NO 834201 A NO834201 A NO 834201A NO 834201 A NO834201 A NO 834201A NO 171094 B NO171094 B NO 171094B
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- NO
- Norway
- Prior art keywords
- oral care
- compound
- agent
- care preparation
- weight
- Prior art date
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- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- LRBQNJMCXXYXIU-NRMVVENXSA-N tannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-NRMVVENXSA-N 0.000 description 1
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- 108700012359 toxins Proteins 0.000 description 1
- GYDJEQRTZSCIOI-LJGSYFOKSA-N tranexamic acid Chemical compound NC[C@H]1CC[C@H](C(O)=O)CC1 GYDJEQRTZSCIOI-LJGSYFOKSA-N 0.000 description 1
- 229960000401 tranexamic acid Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- 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
- 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
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Munnpleiepreparat for behandling av tannkjøttbetenn-else og rothinnebetennelse er særpreget ved at det omfatter en munnpleiemiddelbærer og en effektiv mengde av det vannuopplselige imidazoyl-1-(p-klorfenoxy)-3,3-dimethyl-2-butanon som antigingivittmiddel oppløst i en ikke-ionisk forbindelse som inneholder en blanding av hydrofobe og hydrofile grupper med tilstrekkelig lengde til å bevirke oppløseliggjørelse i en vandig bærer, i vektforholdet oppløseliggjørende middel:imidazoylforbindelse av 1:1-25:1, fortrinnsvis 3:1-25:1.The oral care composition for the treatment of gingivitis and root canal inflammation is characterized in that it comprises an oral care carrier and an effective amount of the water-insoluble imidazoyl-1- (p-chlorophenoxy) -3,3-dimethyl-2-butanone dissolved as a non-antigenic agent. ionic compound containing a mixture of hydrophobic and hydrophilic groups of sufficient length to effect solubilization in an aqueous carrier, in the weight ratio of solubilizing agent: imidazoyl compound of 1: 1-25: 1, preferably 3: 1-25: 1.
Description
Oppfinnelsens bakgrunn The background of the invention
Oppfinnelsen angår fremstilling av et antibakterielt munnpleiepreparat som befordrer munnhygiene og regulerer dannelse av plaque, gingivitt og periodontitt ved topisk anvendelse i munnhulen av et munnvann eller tannrensemiddel som inneholder en effektiv mengde av antigingivittmidlet 1-imidazoyl-l-(p-klorfenoxy)-3,3-dimethyl-2-butanon ("Climbazole") . The invention relates to the production of an antibacterial oral care preparation that promotes oral hygiene and regulates the formation of plaque, gingivitis and periodontitis by topical application in the oral cavity of a mouthwash or dentifrice containing an effective amount of the antigingivitis agent 1-imidazoyl-1-(p-chlorophenoxy)-3, 3-dimethyl-2-butanone ("Climbazole") .
Periodontitt eller pyoré er en sykdom som påvirker tennenes bærevev, innbefattende tannkjøttet, membranen som forer fatningen hvori tennene ligger, og ben som omgir tennene. Sykdommen kan til å begynne med være forbundet med slike betingelser som konstant irritering av tannkjøttet på grunn av tannplaque, fastkiling av mat, dårlig tanngjenopp-bygning, sårinneslutninger eller kjemiske irriterende midler. Periodontitis or pyorrhea is a disease that affects the supporting tissues of the teeth, including the gums, the membrane that lines the socket in which the teeth are located, and the bone that surrounds the teeth. The disease may initially be associated with such conditions as constant irritation of the gums due to dental plaque, wedging of food, poor tooth restoration, wound inclusions or chemical irritants.
Gummene kan bli alvorlig ødelagt av avsetninger av tannplaque som består av en kombinasjon av mineraler og bakterier som forekommer i munnen. De bakterier som er forbundet med plaque, kan utskille enzymer og endotoxiner som irriterer gummene og bevirker in<fl>ammatorisk gumbetennelse. Efterhvert som gummene blir mer og mer irritert på grunn av denne prosess, er de tilbøyelige til å blø, tape sin seighet og fjærende egenskap og skille seg fra tennene efterlatende periodontale lommer hvori avfall, sekreter, The gums can be seriously damaged by deposits of dental plaque which is made up of a combination of minerals and bacteria that occur in the mouth. The bacteria associated with plaque can secrete enzymes and endotoxins that irritate the gums and cause inflammatory gum inflammation. As the gums become more and more irritated due to this process, they tend to bleed, lose their toughness and springiness and separate from the teeth leaving periodontal pockets in which waste, secretions,
flere bakterier og toxiner ytterligere vil ansamles. Det er også mulig at mat akkumulerer i disse lommer og derved gir næring for øtet bakterievekst og produkt av endotoxiner og ødeleggende enzymer. Den materie som dannes under denne prosess, er istand til å ødelegge gummen og benvev. Bakterier er i alminnelighet tilstede under de aktive stadier av periodontal sykdom. Slike organismer som anaerobe gramnegative organismer er vanligvis tilstede og finnes i den materieholdige utsondring og dessuten i det angjeldende vev og kan bli absorbert i det generelle system via den lymfatiske blodstrøm eller veneblodstrøm. more bacteria and toxins will accumulate further. It is also possible that food accumulates in these pockets and thereby provides nourishment for wasted bacterial growth and the production of endotoxins and destructive enzymes. The matter that is formed during this process is capable of destroying the gum and bone tissue. Bacteria are generally present during the active stages of periodontal disease. Such organisms as anaerobic gram-negative organisms are usually present and found in the matter-containing exudate and also in the relevant tissue and can be absorbed into the general system via the lymphatic or venous blood flow.
Utviklingen av pyoréprosessen begynner vanligvis med gumbetennelse som starter ved ytterkantene av gummene hvor tannkjøttet blir mer tandert og ømfintlig og får et slapt, betent og svellet utseende. Periodontale lommer kommer til syne, og infeksjon finner sted i disse lommer. En effektiv kontroll og unngåelse av gumbetennelse utgjør derfor et ønskemål for å kunne hindre ytterligere periodontale sykdommer . The development of the pyorrhea process usually begins with gingivitis that starts at the outer edges of the gums where the gums become more serrated and tender and take on a limp, inflamed and swollen appearance. Periodontal pockets appear, and infection takes place in these pockets. An effective control and avoidance of gingivitis is therefore a desirable goal in order to be able to prevent further periodontal diseases.
En lang rekke materialer er tidligere blitt foreslått og anvendt for å kontrollere munnsykdommer og feilfunksjoner, som plaque, tannsten, vinsten, tannråte, halitosis eller periodontale sykdommer, som tannkjøttbetennelse og pyoré, men ingen av disse har vært fullstendig tilfredsstillende. For eksempel innbefatter munnpleiemidler som inneholder anti-inf lammatoriske midler som reduserer symptcmene med svelling, blødning og betennelse som er forbundet med tannkjøttbe-tennelse ved at vinstendannelse unngås og/eller tannsten mot-virkes, et imidazol, som histadin eller histamin, som beskrevet i US patentskrift 3497591, et diklor-2-guanidin-benzimidazol, som beskrevet i US patentskrift 3523154, carraghenin, som beskrevet i US patentskrift 4029760, en blanding av tranexaminsyre og folinsyre, som beskrevet i US patentskrift 4272512, og garvesyre, som beskrevet i US patentskrift 4273758. Alle de ovennevnte midler er ikke antimikrobielle. A wide variety of materials have previously been proposed and used to control oral diseases and malfunctions, such as plaque, tartar, plaque, tooth decay, halitosis or periodontal diseases, such as gingivitis and pyorrhea, but none of these have been completely satisfactory. For example, oral care compositions containing anti-inflammatory agents that reduce the symptoms of swelling, bleeding and inflammation associated with gingivitis by preventing tartar formation and/or counteracting calculus include an imidazole, such as histadine or histamine, as described in US Patent 3497591, a dichloro-2-guanidine benzimidazole, as described in US Patent 3523154, carrageenan, as described in US Patent 4029760, a mixture of tranexamic acid and folic acid, as described in US Patent 4272512, and tannic acid, as described in US patent document 4273758. All of the above agents are not antimicrobial.
I US patentskrift 3577520 er også et tannrensemiddel beskrevet som inneholder 5,5-diaryl-2,4-imidazolidindioner for behandling av pyorré ved at skadene ved paradontose repareres. US patent 3577520 also describes a dentifrice containing 5,5-diaryl-2,4-imidazolidinediones for the treatment of pyorrhea by repairing the damage caused by periodontitis.
I US patentskrift 3911133 er et antibakterielt middel beskrevet som er effektivt såvel mot grampositive som gramnegative bakterier og omfatter et imidazolderivat som er et kvartært bis-imidazoliumsalt som er nyttig i munnvann, tannpastaer og tanngeler ved at det hemmer dannelsen av tannplaque og dermed tannkjøttbetennelse. In US patent 3911133, an antibacterial agent is described which is effective against both gram-positive and gram-negative bacteria and comprises an imidazole derivative which is a quaternary bis-imidazolium salt which is useful in mouthwashes, toothpastes and dental gels in that it inhibits the formation of dental plaque and thus gingivitis.
I US patentskrift 4243670 er imidazoliumderivater beskrevet med sterk antimikrobiell virkning overfor dermato-fytter, gjær, sopper, bifasede fungi og grampositive kokker, og de er dessuten anvendbare som tilsetningsmiddel til munn-hygieneprodukter, som tannpastaer og munnvann, for å unngå mikrobielt forårsakede infeksjoner i munnens slimhinne og In US patent 4243670, imidazolium derivatives are described with strong antimicrobial action against dermatophytes, yeasts, fungi, biphasic fungi and Gram-positive cocci, and they are also usable as additives to oral hygiene products, such as toothpastes and mouthwashes, to avoid microbially caused infections in the mucous membrane of the mouth and
som profylaktisk middel mot infeksjon. as a prophylactic agent against infection.
Det er også kjent innen, den angjeldende teknikk at It is also known within, the relevant technique that
visse gramnegative organismer, som Bacteri"odes asaccharolyticus eller Bacteriodes gingivalis,er forbundet med periodontitt hos voksne mennesker. Dersom disse og andre gramnegative anaerobe organismer elimineres fra plaque akkumulert på gumvevet, kan effektiv kontroll og unngåelse av periodontal sykdom oppnås. certain gram-negative organisms, such as Bacteri"odes asaccharolyticus or Bacteriodes gingivalis, are associated with periodontitis in adults. If these and other gram-negative anaerobic organisms are eliminated from plaque accumulated on the gum tissue, effective control and avoidance of periodontal disease can be achieved.
Det er derfor blitt påvist av Listgarton og medarbeidere i J. Periodont. Res. 14: 65-75 (1979), at metronidazol It has therefore been demonstrated by Listgarton and colleagues in J. Periodont. Res. 14: 65-75 (1979), that metronidazole
gitt systemisk forårsaker eliminering av de gramnegative anaerobe organismer fra plaque. Dette ble bekreftet av Heijl og Lindhe i J. Clinical Periodontology 6, 197-209 given systemically causes the elimination of the gram-negative anaerobic organisms from the plaque. This was confirmed by Heijl and Lindhe in J. Clinical Periodontology 6, 197-209
(1979), som påviste at metronidazol er effektivt hva gjelder (1979), who demonstrated that metronidazole is effective as far as
å redusere plaque og dermed tannkjøttsår hos hunder, og av Loesche og medarbeidere i J. of Clinical Periodontology, 8: 29-44 to reduce plaque and thus gum ulcers in dogs, and by Loesche and colleagues in J. of Clinical Periodontology, 8: 29-44
(1981), som påviste at metronidazol er effektivt hva gjelder (1981), who demonstrated that metronidazole is effective as far as
å redusere antallet av anaerobt B. asaccharolyticus i plaque som er blitt fjernet fra tannkjøttlommer, samtidig med en vesentlig reduksjon av lommenes dybde og betydelig økning av det tilsynelatende feste. Metronidazol som selges under varemerket 'Flagyl", er imidlertid carcinogent (Physician Reference Handbook s. 1761) og kan ikke anvendes vilkårlig. to reduce the number of anaerobic B. asaccharolyticus in plaque that has been removed from gum pockets, at the same time as significantly reducing the depth of the pockets and significantly increasing the apparent attachment. However, metronidazole, which is sold under the brand name 'Flagyl', is carcinogenic (Physician Reference Handbook p. 1761) and cannot be used indiscriminately.
Det har nå vist seg at et annet derivat av imidazol virker effektivt mot de nevnte gramnegative anaerobe organismer, og derivatet er ikke-mutagent, ikke-carcinogent og kan gis topisk i munnhulen i tilfelle av forekommende tannkjøttbe-tennelse, og derivatet utgjøres nærmere bestemt av 1-imidazoyl-1-(p-klorfenoxy)-3,3-dimethyl-2-butanon. It has now been shown that another derivative of imidazole works effectively against the aforementioned gram-negative anaerobic organisms, and the derivative is non-mutagenic, non-carcinogenic and can be given topically in the oral cavity in the event of gingivitis occurring, and the derivative is more precisely constituted by 1-Imidazoyl-1-(p-chlorophenoxy)-3,3-dimethyl-2-butanone.
Imidazoylketonene, som 1-imidazoyl-l-(4-klorfenoxy)-3,3-dimethyl-2-butanon, er beskrevet i US patentskrifter 3812142 og 3903287 som et anti-mykotisk middel som kan anvendes i farmasøytiske preparater,innbefattende pastaer, geler, kremer eller vandige eller ikke vandige suspensjoner. Dets virkning mot patogent protozoa, grampositive og -negative bakterier, som Staphlococci og Escherichia coli, er også angitt i disse patentskrifter. The imidazoyl ketones, such as 1-imidazoyl-1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone, are described in US Patents 3812142 and 3903287 as an anti-mycotic agent that can be used in pharmaceutical preparations, including pastes, gels , creams or aqueous or non-aqueous suspensions. Its action against pathogenic protozoa, gram-positive and -negative bacteria, such as staphlococci and Escherichia coli, is also indicated in these patents.
I britisk patentskrift 1502144 og i det tilsvarende vest-tyske patentskrift 2430039 er hår- eller hudbehandlings-preparater beskrevet som er effektive mot Pityrosporum ovale og inneholder de antimykotiske imidazoylketonmidler dispergert i en dermatologisk aksepterbar bærer som inneholder en aktiv renseforbindelse. Disse preparater forelig-ger i form av kremer, aerosoler, pulver eller væsker. I vest-tysk patentskrift 2600800 er 1-imidazoyl -1-(4-klorfenoxy)-3,3-dimethyl-2-butanon i et fungicidpreparat beskrevet, enten i tørr form, som en dispersjon i vann, som en vann-i-olje-eller en olje-i-vannemulsjon eller et dusjpreparat, som er nyttig for å beskytte gipsbelegg, dispersjonsfarvestoffer, tapeter, flisebelagte overflater, malinger, lim, bitumina, møbler, lær, dusj forheng, tekstiler, tepper, treverk og papir mot en lang liste av patogene fungi, mugg og bakterier. Det finnes imidlertid ingen omtale av Bacteroides asaccharolyticus eller gingivalis, som er de spesielle anaeorobe gramnegative organismer som finnes i plaque ved tannkjøttbetennelse. I vest-tysk patentskrift 27009806 er også en blanding av imidazoylketonfungicidet og et kvartært ammoniumbactericid beskrevet som er nyttig for å beskytte slike materialer som maling, lim, bitumen, cellulose, papir, tekstiler, lær eller tre.. In British patent document 1502144 and in the corresponding West German patent document 2430039, hair or skin treatment preparations are described which are effective against Pityrosporum ovale and contain the antifungal imidazoyl ketone agents dispersed in a dermatologically acceptable carrier which contains an active cleansing compound. These preparations are available in the form of creams, aerosols, powders or liquids. In West German patent document 2600800, 1-imidazoyl -1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone in a fungicide preparation is described, either in dry form, as a dispersion in water, as a water-in- oil or an oil-in-water emulsion or a shower preparation, which is useful for protecting plaster coatings, dispersion dyes, wallpaper, tiled surfaces, paints, adhesives, bituminous, furniture, leather, shower curtains, textiles, carpets, wood and paper against a long list of pathogenic fungi, mold and bacteria. However, there is no mention of Bacteroides asaccharolyticus or gingivalis, which are the special anaerobic Gram-negative organisms found in plaque in gingivitis. In West German patent document 27009806, a mixture of the imidazoyl ketone fungicide and a quaternary ammonium bactericide is also described which is useful for protecting such materials as paint, glue, bitumen, cellulose, paper, textiles, leather or wood.
Selv om det spesifiserte imidazoylketon i teknikkens stand er beskrevet som et antimykotisk middel og dessuten anvendelse av dette i farmasøytiske preparater, spesielt i hår- og hudpleiepreparater, forekommer ingen angivelse av en anvendelse av dette i tannpleiemidler og heller ikke at det skulle være effektivt mot de spesifikke gramnegative anaerobe organismer som er forbundet med gingivitt og periodontitt. Although the specified imidazoyl ketone is described in the state of the art as an antifungal agent and furthermore its use in pharmaceutical preparations, especially in hair and skin care preparations, there is no indication of its use in dentifrices nor that it should be effective against the specific gram-negative anaerobic organisms associated with gingivitis and periodontitis.
Beskrivelse av oppfinnelsen Description of the invention
Det har nå vist seg at det vannuoppløselige imidazoylketon 1-imidazoyl-l-(p-klorfenoxy)-3,3-dimethyl-2-butanon virker selektivt mot de i tannplaque forekommende spesifikke anaerobe gramnegative organismer som er forbundet med gingivitt, når det anvendes topisk i munnhulen. It has now been shown that the water-insoluble imidazoyl ketone 1-imidazoyl-1-(p-chlorophenoxy)-3,3-dimethyl-2-butanone acts selectively against the specific anaerobic gram-negative organisms found in dental plaque that are associated with gingivitis, when used topically in the oral cavity.
Det er derfor et hovedformål ved oppfinnelsen å fremstille et munnpleiepreparat som inneholder det ovennevnte vannuoppløselige imidazoylketon som antigingivittmiddel som er oppløst i en munnpleiepreparatbærer. It is therefore a main object of the invention to produce an oral care preparation containing the above-mentioned water-insoluble imidazolyl ketone as an antigingivitis agent which is dissolved in an oral care preparation carrier.
Det tas ved oppfinnelsen også sikte på å fremstille et munnskyllevann eller tannrensemiddel som effektivt vil kontrollere og behandle plaque, gingivitt og periodontitt. The invention also aims to produce a mouthwash or dentifrice which will effectively control and treat plaque, gingivitis and periodontitis.
Det tas ved oppfinnelsen videre sikte på å fremstille The invention further aims to produce
et munnpleiepreparat som inneholder det ovennevnte antigingivittmiddel oppløst i en vandig bærer som omfatter en ikke-ionisk forbindelse. an oral care preparation containing the above-mentioned antigingivitis agent dissolved in an aqueous carrier comprising a non-ionic compound.
Det er et ytterligere formål ved oppfinnelsen å fremstille et antibakterielt munnpleiepreparat som kan anvendes for å hindre og behandle gingivitt hos. dyr. It is a further object of the invention to produce an antibacterial oral care preparation which can be used to prevent and treat gingivitis in. animals.
Den foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av et munnpleiepreparat for kontroll av plaque, gingivitt og periodontitt, og fremgangsmåten er særpreget ved at The present invention relates to a method for producing an oral care preparation for the control of plaque, gingivitis and periodontitis, and the method is characterized by the fact that
(A) vannuoppløselig 1-imidazoyl-l-(p-klorfenoxy)-3,3-dimethyl-2-butanonforbindelse først oppløseliggjøres ved å (A) water-insoluble 1-imidazoyl-1-(p-chlorophenoxy)-3,3-dimethyl-2-butanone compound is first solubilized by
blande forbindelsen med et ikke-ionisk overflateaktivt opp-løseliggjørende middel eller et ikke-ionisk fuktighetsbevarende oppløseliggjørende middel i et vektforhold mellom midlet og forbindelsen av fra 1:1 til 25:1, hvoretter mixing the compound with a nonionic surfactant solubilizing agent or a nonionic humectant solubilizing agent in a weight ratio of the agent to the compound of from 1:1 to 25:1, then
(B) den resulterende blanding oppløses i en oralt aksep-tabel vandig bærer i en slik mengde at munnpleiepreparatetE.får (B) the resulting mixture is dissolved in an orally acceptable aqueous carrier in such an amount that the oral care preparation E. receives
et innhold av 0,1-5 vekt% av den nevnte forbindelse. a content of 0.1-5% by weight of the said compound.
Et vektforhold av 3:1-25:1 mellom ikke ionisk middel og den nevnte forbindelse er foretrukket. A weight ratio of 3:1-25:1 between non-ionic agent and said compound is preferred.
For å bevirke påfølgende oppløseliggjørelse i den vandige bærer inneholder det ikke-ioniske middel fortrinnsvis et hydrofobt polyoxypropylenradikal og 10-80 vekt% hydrofile polyoxyethylenradikaler med tilstrekkelig lengde til å bevirke oppløseliggjørelse av imidazoylforbindelsen i en vandig bærer, idet prosentforholdet mellom hydrofile og hydrofobe radikaler i det ikke-ioniske middel fortrinnsvis er ca. 4:1. To effect subsequent solubilization in the aqueous carrier, the nonionic agent preferably contains a hydrophobic polyoxypropylene radical and 10-80% by weight of hydrophilic polyoxyethylene radicals of sufficient length to effect solubilization of the imidazolyl compound in an aqueous carrier, the percentage ratio between hydrophilic and hydrophobic radicals in the non-ionic agents are preferably approx. 4:1.
Munnpleiepreparatbæreren kan være væske, som et munnvann eller munnskyllevann, et fast materiale som tyggegummi eller tannpulver, eller et pastalignende eller kremlignende materiale, som en tannpasta eller en tannkrem. The oral care preparation carrier can be a liquid, such as a mouthwash or mouthwash, a solid material such as chewing gum or tooth powder, or a paste-like or cream-like material, such as a toothpaste or a toothpaste.
Et munnvann fremstilt ifølge oppfinnelsen har en pH A mouthwash produced according to the invention has a pH
av 5-7,5 og en vandig alkoholholdig bærer som inneholder et ikke-ionisk overflateaktivt middel som det ikke-ioniske opp-løseligg j ørende middel for den antibakterielle forbindelse og valgt fra gruppen bestående av blokkpolymeren av propylenoxyd og ethylenoxyd, polyoxyethylenhexitan-mono-høyere-fett-syreestere inneholdende 10-8 0 mol ethylenoxyd pr. mol eller blandinger derav. of 5-7.5 and an aqueous alcoholic carrier containing a nonionic surfactant as the nonionic solubilizing agent for the antibacterial compound and selected from the group consisting of the block polymer of propylene oxide and ethylene oxide, polyoxyethylenehexitan-mono- higher fatty acid esters containing 10-8 0 mol of ethylene oxide per moles or mixtures thereof.
Det typiske overflateaktive middel inneholder minst 10-80 vekt% hydrofile enheter av polyoxyethylen i forhold til det hydrofobe radikal, som polyoxypropylen, som fortrinnsvis har en molekylvekt av ca. 3250, som f.eks. for de blandede polymerer av propylenoxyd og ethylenoxyd. Forholdet mellom oppløseliggjørende materiale og imidazolforbindelse er fortrinnsvis 3:1-25:1. Ved forhold over 25:1 inntrer geldannelse. The typical surfactant contains at least 10-80% by weight of hydrophilic units of polyoxyethylene in relation to the hydrophobic radical, such as polyoxypropylene, which preferably has a molecular weight of approx. 3250, such as for the mixed polymers of propylene oxide and ethylene oxide. The ratio between solubilizing material and imidazole compound is preferably 3:1-25:1. At ratios above 25:1 gel formation occurs.
En tannpasta fremstilt ifølge oppfinnelsen har A toothpaste produced according to the invention has
en pH av 5 - 7,5 og tannpastaen inneholder et tann-pleiemessig aksepterbart poleringsmateriale, a pH of 5 - 7.5 and the toothpaste contains a dental care-acceptable polishing material,
en flytende bærer som omfatter vann,og en effektiv mengde av 0,1-5 vekt% av det vannuoppløselig antibakterielle middel 1-imidazoyl-l-(p-klorfenoxy)-3,3-dimethyl-2-butanon oppløst i 20-40 vekt% av preparatet av et ikke-ionisk fuktighetsbevarende middel som innbefatter minst ett fuktighetsbevarende middel fra gruppen bestående av polyoxyethylenglycol og polyoxypropylenglycol i vektforholdet 3:1-25:1 mellom ikke-ionisk fuktighetsbevarende middel og antibakterielt middel. a liquid carrier comprising water and an effective amount of 0.1-5% by weight of the water-insoluble antibacterial agent 1-imidazoyl-1-(p-chlorophenoxy)-3,3-dimethyl-2-butanone dissolved in 20-40 % by weight of the preparation of a non-ionic humectant which includes at least one humectant from the group consisting of polyoxyethylene glycol and polyoxypropylene glycol in the weight ratio of 3:1-25:1 between non-ionic humectant and antibacterial agent.
Det antibakterielle middel virker selektivt mot de gramnegative, anaerobe mikroorganismer Bacteriodes assaccharolyticus, Bacteroides gingivalis eller blandinger derav. The antibacterial agent acts selectively against the Gram-negative, anaerobic microorganisms Bacteriodes assaccharolyticus, Bacteroides gingivalis or mixtures thereof.
Glycerol, sorbitol eller mannitol kan anvendes som delvis erstatning for det fuktighetsbevarende middel,forutsatt at det antibakterielle middel er blitt oppløseliggjort. Glycerol, sorbitol or mannitol can be used as a partial replacement for the humectant, provided that the antibacterial agent has been solubilized.
Antigingivittmidlet som anvendes i munnpleiepreparatene fremstilt ifølge oppfinnelsen, er l-imidazoyl-l-(p-klor-fenoxy)-3 ,3-dimethyl-2-butanon med strukturformelen The antigingivitis agent used in the oral care preparations produced according to the invention is 1-imidazoyl-1-(p-chloro-phenoxy)-3,3-dimethyl-2-butanone with the structural formula
som fremstilles ved å omsette 1-brom-l-(4-klorfenoxy)-3,3-dimethyl-2-butanon med imidazol oppløst i acetonitril, which is prepared by reacting 1-bromo-1-(4-chlorophenoxy)-3,3-dimethyl-2-butanone with imidazole dissolved in acetonitrile,
som beskrevet i US patentskrifter 3812142 og 3903287. Dette imidazoylketon er et vannuoppløselig, krystallinsk pulver med et smeltepunkt av 94,5-97,8°C og er tilgjengelig i handelen under varemerket "Climbazole". På grunn av denne imidazolforbindelses vannuoppløselighet må den først gjøres oppløselig i en ikke-ionisk forbindelse før ioniserte materialer tilsettes i et vandig medium. as described in US Patents 3812142 and 3903287. This imidazoyl ketone is a water-insoluble, crystalline powder with a melting point of 94.5-97.8°C and is commercially available under the trademark "Climbazole". Because of this imidazole compound's water insolubility, it must first be made soluble in a nonionic compound before ionized materials are added to an aqueous medium.
Det har overraskende vist seg at denne antibakterielle forbindelse tilsatt til munnpleiepreparatbærere ikke bare virker effektivt mot de spesifikke anaerobe organismer som forekommer ved tannsykdommen periodontitt,men at den også reduserer sykdommen sterkt når den tilføres topisk, og at den dessuten reduserer symptomene på gingivitt som er forbundet med periodontitt. Den minste inhibitérende konsentrasjon (MIC) som er nødvendig for å drepe Bacteroides assaccharolyticus (Forsyth-stamme), bestemt i overensstemmelse med metoden ifølge Walker og medarbeidere (Antimicrobial and Chemotherapy, Vol.16, s. 452-457, 1979), er mellom 7,8 og 31,2 mikro- It has surprisingly been shown that this antibacterial compound added to oral care preparation carriers is not only effective against the specific anaerobic organisms that occur in the dental disease periodontitis, but that it also greatly reduces the disease when applied topically, and that it also reduces the symptoms of gingivitis associated with periodontitis. The minimum inhibitory concentration (MIC) required to kill Bacteroides assaccharolyticus (Forsyth strain), determined in accordance with the method of Walker et al. (Antimicrobial and Chemotherapy, Vol.16, pp. 452-457, 1979), is between 7.8 and 31.2 micro-
gram pr. ml MIC-verdien for B. gingivalis er 25 mikrogram grams per ml The MIC value for B. gingivalis is 25 micrograms
pr. ml MIC-verdien for B. gracilis og Fusobacterium som er andre gramnegative organismer, er over 50 for hver, og MIC-verdien for den grampositive organisme Actinomyces viscosus er 125 for den aerobe stamme og 250 for den anaerobe stamme. Dette antyder klart selektiviteten hva gjelder den antibakterielle aktivitet til den spesifikke imidazolforbineelse som anvendes i de foreliggende munnpleiepreparater som antigingivittmiddel. per The ml MIC value for B. gracilis and Fusobacterium, which are other gram-negative organisms, is above 50 for each, and the MIC value for the gram-positive organism Actinomyces viscosus is 125 for the aerobic strain and 250 for the anaerobic strain. This clearly suggests the selectivity in terms of the antibacterial activity of the specific imidazole compound used in the present oral care preparations as an antigingivitis agent.
En vurdering av munnpleiepreparater mot gingivitt under anvendelse av et 0,3% Climbazole-holdig munnskylle- An evaluation of oral care preparations against gingivitis using a 0.3% Climbazole-containing mouthwash
vann foretatt ved en undersøkelse ctv 30 beagle-hunder i 10 uker viser klart dets overlegne virkning. water carried out in a study on 30 beagle dogs for 10 weeks clearly shows its superior effect.
Den anvendte metode innbefatter fullstendig fjernelse av hårde og myke tannavsetninger, hvorefter hundene holdes på bløt diett i 6 uker for at gingivitt skal kunne utvikles. Tannsettene blir derefter behandlet med prøveoppløsningene to ganger daglig, 5 dager pr. uke, i ca. 15 s på hver side av munnen. Dyrene undersøkes, og graden av tannkjøtt-inflammasjon gis poengtall i overensstemmelse med en skala fra 0 til 3, hvor 0 = ingen inflammasjon, 1 = mild, lokal ødem og rødhet i tannkjøttkanten, ingen blødning fremkalles ved forsiktig ^rykk med fingrene, 2 = moderat ødem og rødhet i tannkjøttkanten med bløding ved forsiktig trykk med fingrene, 3 = alvorlig ødem og kronisk sårdannelse i tannkjøttkantene og angrepet tannkjøtt, og blødning uten forsiktig trykk med fingrene. Et virkningsløst munnskyllevann og et 0,5% metronidazolmunnskyllevann ble anvendt for hhv. de negative og de positive kontroller. Dataene er oppsummert i tabell 1. The method used involves the complete removal of hard and soft dental deposits, after which the dogs are kept on a soft diet for 6 weeks to allow gingivitis to develop. The sets of teeth are then treated with the sample solutions twice a day, 5 days per week, for approx. 15 s on each side of the mouth. The animals are examined, and the degree of gum inflammation is given a score in accordance with a scale from 0 to 3, where 0 = no inflammation, 1 = mild, local edema and redness at the gum edge, no bleeding is elicited by gentle tugging with the fingers, 2 = moderate edema and redness of the gum line with bleeding when gently pressed with the fingers, 3 = severe edema and chronic ulceration of the gum line and affected gums, and bleeding without gentle finger pressure. An ineffective mouthwash and a 0.5% metronidazole mouthwash were used for, respectively. the negative and the positive controls. The data are summarized in Table 1.
Sammenlignet med placeboskyllevannet (det virkningsløse middel) reduserte såvel Metronidazole- som Climbazole-skyllevann utviklingen av tannkjøttenheten 2 betydelig. Imidlertid ga en mindre mengde (0,3%) av Climbazole den samme virkning mot gingivitt som større mengder (0,5%) av Metronidazole. Compared to the placebo rinse (the ineffective agent), both Metronidazole and Climbazole rinses significantly reduced the development of gingival unit 2. However, a smaller amount (0.3%) of Climbazole produced the same effect against gingivitis as larger amounts (0.5%) of Metronidazole.
Selv om Metronidazole er effektivt mot de spesifikke gramnegative mikroorganismer som er involvert ved periodontal sykdom når det anvendes systemisk, som omfattende behandlet i teknikkens stand, virker det imidlertid ikke like godt når det tilføres topisk. Grunnen til de dårlige resultater skyldes fraværet i dets strukturformel av en egnet hydrofob gruppe som er nødvendig for å trenge inn i tannkjøttvevet. Derimot inneholder Climbazole en voluminøs hydrofob gruppe, (p-klorfenoxy)-3/3-dimethyl-2-butanon, som gir god inntreng-ning i vevet på de steder hvor den ødeleggende periodontitt-prosess finner sted, slik at dette antibakterielle middel vil opprettholde en slik effektiv konsentrasjon at bakterie-antallet av de gramnegative, anaerobe mikroorganismer forbundet med denne sykdom vil bli redusert. Dessuten er Metronidazole mutagent på grunn av dets nitrogruppe, mens Climbazole ikke er mutagent ved mutagene forsøk fordi det mangler nitrogruppen, hvilket fremgår av de nedenfor angitte strukturformler: Although Metronidazole is effective against the specific Gram-negative microorganisms involved in periodontal disease when used systemically, as extensively treated in the prior art, it does not work as well when applied topically. The reason for the poor results is due to the absence in its structural formula of a suitable hydrophobic group which is necessary to penetrate the gum tissue. In contrast, Climbazole contains a bulky hydrophobic group, (p-chlorophenoxy)-3/3-dimethyl-2-butanone, which provides good penetration into the tissue in the places where the destructive periodontitis process takes place, so that this antibacterial agent will maintain such an effective concentration that the bacterial count of the gram-negative, anaerobic microorganisms associated with this disease will be reduced. Also, Metronidazole is mutagenic because of its nitro group, while Climbazole is not mutagenic in mutagenic tests because it lacks the nitro group, as evidenced by the structural formulas given below:
Munnpleiepreparatene fremstilt ifølge oppfinnelsen kan være flytende, som et munnvann eller skyllevann. I slike preparater utgjøres bæreren typisk av en vann-alkoholblandlng. Forholdet mellom vann og alkohol ligger i alminnellqhet innen området 1:1-20:1, fortrinnsvis 3:1-20:1, basert på vekt. Alkoholinn-holdet utgjør fortrinnsvis 20-40 vekt% av b#rcren. Den sam-lede mengde av vann-alkoholblanding i denne type av preparater ligger typisk innen området 70-98 vekt% av preparatet. En slik væske og andre preparater fremstilt ifølge oppfinnelsen vil i alminnelighet ha en pH innen området S-7,5. The oral care preparations produced according to the invention can be liquid, such as a mouthwash or rinse. In such preparations, the carrier typically consists of a water-alcohol mixture. The ratio between water and alcohol is generally in the range 1:1-20:1, preferably 3:1-20:1, based on weight. The alcohol content is preferably 20-40% by weight of the beer. The total amount of water-alcohol mixture in this type of preparation is typically in the range of 70-98% by weight of the preparation. Such a liquid and other preparations produced according to the invention will generally have a pH within the range S-7.5.
En vesentlig komponent i de flytende runr.pleie-preparater er 1-5 vekt% av et ikke ionisk over f 1ateaktivt middel som inneholder 10-80 vekt% hydrofile enheter av polyoxyethylen og også hydrofobt polyoxypropylen eller høyere fettsyre,-fettester eller fettamid, for å opp-løseliggjøre det vannuoppløselige Climbazole- i den vandige alkoholbærer. An essential component in the liquid skin care preparations is 1-5% by weight of a non-ionic surfactant containing 10-80% by weight of hydrophilic units of polyoxyethylene and also hydrophobic polyoxypropylene or higher fatty acids, fatty esters or fatty amides, for to solubilize the water-insoluble Climbazole in the aqueous alcohol carrier.
Egnede ikke-ioniske overflateaktive midler innbefatter blokkpolymerer av ethylenoxyd, blandede propylenoxyd-ethylen-oxydpolymerer, polyoxyethylenhexitan-mono-høyere fettsyre-estere med 10-20 carbonatomer i den høyere fettacylgruppe og 4-100, fortrinnsvis 10-80, mol ethylenoxyd pr. molekyl. Hexitanet utgjøres fortrinnsvis av sorbitan selv om mannitan eller andre hexitaner også ofte kan anvendes, og den høyere fettacylgruppe vil ha 10-16 eller 20 carbonatomer, mer foretrukket 12-16 eller 18 carbonatomer, og helst ca. 12 carbonatomer, og antallet av ethoxygrupper vil være 15-80, ofte fortrinnsvis ca. 20. Spesielt anvendbart er et produkt som Suitable nonionic surfactants include block polymers of ethylene oxide, mixed propylene oxide-ethylene oxide polymers, polyoxyethylenehexitane mono-higher fatty acid esters with 10-20 carbon atoms in the higher fatty acyl group and 4-100, preferably 10-80, moles of ethylene oxide per molecule. The hexitan is preferably made up of sorbitan, although mannitan or other hexitans can also often be used, and the higher fatty acyl group will have 10-16 or 20 carbon atoms, more preferably 12-16 or 18 carbon atoms, and preferably approx. 12 carbon atoms, and the number of ethoxy groups will be 15-80, often preferably approx. 20. Particularly applicable is a product which
(r) (s)
selges under varemerket Tweerr<*> 20 som også er kjent som "Polysorbate 20" som er polyoxyethylen '(20)-sorbitanmono-laurat. ;Lignende anvendbare produkter selges under lignende be-(b) ;tegnelser, som Tween 40, 60, 65 eller 80, og alle disse er ikke-ioniske overflateaktive midler hvori den høyere fettacylgruppe er palmitoyl, stearoyl eller oleyoyl og antallet av mol ethylenoxyd pr. molekyl er ca. 20. Blant disse materialer blir imidlertid som regel polyoxyethylensorbitanmono-lauratet foretrukket. Polyoxyethylen (80)-sorbitanmono-laurat kan anvendes istedenfor den nevnte "Polysorbate 20". ;Andre egnede ikke-ioniske, overflateaktive midler innbefatter mono- eller .diethanolamidene av høyere fettsyrer med 10-18 carbonatomer i acylgruppen, som kokosmcnoethanolamid, kokosdiethanolamid, laurin-myristindiethanolamid, laurinmono-ethanolamid ellerkombinasjoner derav. ;De ifølge oppfinnelsen, fremstilte munnpleiepreparater kan være i det vesentlige pastalignende, som en tannpasta eller en tannkrem. ;Bæreren i slike pastalignende munnpleiepreparater inneholder poleringsmateriale. Eksempler på poleringsmaterialer er vann-uoppløselig natriummetafosfat, kaliummetafosfat, trikalsium-fosfat, kalsiumpyrofosfat, mågnesiumorthofosfat, trimagnesium-fosfat, kalsiumcarbonat, aluminiumoxyd, hydratisert aluminiumoxyd, aluminiumsilikat, zirkoniumsilikater, siliciumdioxyd-bentonitt, krystallinsk siliciumdioxyd med partikler med størrelser opp til 5yum, silikagel, komplekst amorft alkali-metallaluminiumsilikat, hydratisert aluminiumoxyd, dikalsium-fosfat eller blandinger derav. ;Når visuelt klare geler fremstilles, er et poleringsmid.de 1 av kolloidalt siliciumdioxyd, som det som selges under varemerket Syloid®, som Syloicr^ 72 eller Syloi"d®74, eller under varemerket Santocel , som SantoceP^ 100, eller alkalimetall-aluminiumsilikatkomplekser spesielt anvendbare fordi de har brytningsindekser som ligger nær brytningsindeksene for gel-middel-væske (innbefattende vann og/eller fuktighetsbevarende middel)-systemene som er vanlig anvendt i tannpleiemidler. ;Poleringsmaterialet er i alminnelighet tilstede i en mengde av 10-99 vekt% av munnpleiepreparatet. Det er fortrinnsvis tilstede i en mengde av 10-75% i en tannpasta. ;I en tannpasta omfatter den flytende bærer vann og fuktighetsbevarende middel typisk i en mengde av 10-90 vekt% av preparatet. En vesentlig komponent i tannpastaen og i tannkrem er 20-4 0 vekt% av et ikke-ionisk fuktighetsbevarende middel innbefattende minst ett av polyethylenglycol eller polypropylenglycol for å gjøre det vannuoppløselige Climbazole oppløselig i den vandige bærer. Glycerol, sorbitol eller mannitol kan anvendes istedenfor en del av det fuktighetsbevarende middel, forutsatt at imidazolforbindelsen er opp-løseligg jort i polyoxyethylen- eller polyoxypropylenglycolen. ;Et geimiadei, som naturlige eller syntetiske gummier eller gummier eller gummilignende materialer, typisk irsk mose, natriumcarboxymethylcellulose, methylcellulose, hydroxyethyl-cellulose, tragantgummi, polyvinylpyrrolidon, stivelse eller hydroxypropylmethylcellulose, er som regel tilstede i tannpastaer i en mengde opp til 1 vekt%, fortrinnsvis innen området 0,5-5 vekt%. I en tannpasta eller gel blir væskene og de faste stoffer anvendt i slike forholdsvise mengder at det dannes en kremlignende eller gelert masse som kan ekstruderes fra en trykkbeholder eller fra en sammenklembar tube av f.eks. aluminium eller bly. ;Munnpleiepreparatene fremstilt ifølge o<p>pfinnelsen kan inneholde et syntetisk, tilstrekkelig vannoppløselig, organisk, ;anionisk eller ikke-ionisk overflateaktivt middel som ikke er såpe, i konsentrasjoner av 1-5 vekt% for å befordre fukt- ;ning, rensekraft og skumdårmelse. I US patentskrift 4041149 er slike egnede anioniske overflateaktive midler beskrevet i spalte 4, linjene 31-38, og slike egnede ikke-ioniske overflateaktive midler er beskrevet i spalte 8, linjene 30-68, ;og i spalte 9, linjene 1-12. ;Munnpleie<p>reparatene fremstilt ifølge oppfinnelsen som inneholder det antibakterielle middel, kan eventuelt inneholde en fluoravgivende forbindelse, innbefattende uorganiske fluoridsalter, som oppløselig alkalimetall-, jordalkalimetall- eller tung-metallsalter, f.eks. natriumfluorid, kaliumfluorid, ammonium-fluorid, kalsiumfluorid, et kobberfluorid, som énverdig kobberfluorid, sinkfluorid, et tinnfluorid, som fireverdig tinnfluorid eller toverdig tinnklorfluorid, bariumfluorid, natriumfluorsilikat, ammoniumfluorisilikat, natriumfluor-zirkonat, natriummonoflucrfosfat, aluminium-mono- eller -difluorfosfat eller fluorert natrium-kalsiumpyrofosfat. 'Alkalimetall- og tinnfluorider, som natrium- eller toverdige tinnfluorider, natriummonofluorfosfat eller blandinger derav, er foretrukne. ;Mengden av den fluoravgivende forbindelse er i en viss grad avhengig av typen av forbindelse, dens oppløselighet og typen av munnpleiemidlet, men mengden må være en ugiftig mengde. I et fast munnpleiepreparat, som en tannpasta eller tyggegummi, betraktes en mengde av en slik forbindelse som vil avgi maksimalt 1 vekt% fluor i forhold til preparatet, ;som tilfredsstillende. En hvilken som helst egnet minstemengde av en slik forbindelse kan anvendes, men det f oretre.kke s å anvende tilstrekkelig med forbindelsen til at 0,005-1, fortrinnvis ca. 0,1, % fluoridioner vil bli avgitt. For alkalimetallfluorider og toverdig tinnfluorid er denne komponent typisk tilstede i en mengde opp til 2 vekt%, basert på vekten av preparatet, og fortrinnsvis innen området 0,05-1 vekt%. For natriummonofluorfosfat kan denne komponent være tilstede i en mengde opp til 7,6 vekt%, mer typisk ca. 0,76%. ;Forskjellige andre materialer kan innarbeides i munnpleiepreparatene fremstilt ifølge oppfinnelsen som ikke uheldig påvirker preparatenes egenskaper, som søtningsmidlér (f.eks. saccharin, sucrose, lactose, maltose eller sorbitol etc), smaksoljer (f.eks. oljer av grønn mynte, peppermynte, vintergrønt, sassafran, kryddernellik, salvie, eucalyptus, ir.erian, kanel, sitron eller appelsin etc), farve- eller hvitemidler (f.eks. titandioxyd) eller konserveringsmidler (f.eks. natriumbenzoat) etc. Mindre mengder av samlet opp til 5 vekt%, fortrinnsvis 0,01-3 vekt%, av disse materialer kan tilsettes til munnpleiepreparatet. ;De ved den foreliggende fremgangsmåte fremstilte munnpleiepreparater kan enkelt fremstilles ved hjelp av enkle blandemetoder ut fra lett tilgjenge 1iqe komponenter. Det er imidlertid av vesentlig betydning at irtidazoylfor-bindelsen først blandes med den ikke-ioniske komponent før den tilsettes til munnpleiemiddelbæreren som i r.nbe f atter vann. ;For eksempel kan et munnskyllevann eller munnvann fremstilles ved først å gjøre imidazolforbinde1 sen oppløselig ved å emulgere denne i et ikke-ionisk overflateaktivt niddel før tilsetning til den vandige eller alkoholisk-vandige bærer. ;De andre bestanddeler, som smaksmidler eller sctningsmidler etc, kan tilsettes til den vandige bærer fer eller efter til-setningen av det oppløseliggjorte imidazol til den vandige bærer. ;Tannpastaen kan fremstilles ved først å blande imidazolforbindelsen med-det fuktighetsbevarende middel som er ikke-ionisk, hvori den blir oppløseliggjort, for derefter å til-sette fortykningsmidlet, f.eks. carboxymethyleellulose for dannelse av en gel, fulgt av tilsetning av poleringsmiddel, ;vann og andre bestanddeler. Tilsetningsrekkefølgen for de forskjellige bestanddeler kan varieres, forutsatt at imidazolforbindelsen først blir oppløseliggjort i det ikke-ioniske fuktighetsbevarende middel før vannkomponenten tilsettes. ;Et munnpleiepreparat fremstilt ifølge oppfinnelsen, som et munnvann eller en tannpasta, som inneholder 1-imidazoyl-l-(p-klor-f enoxy)-3, 3-dimethyl-2-butanon som antigingivitt middel i en mengde som effektivt vil befordre munnhygienen, blir regelmessig påført på tannemalje, fortrinnsvis 1-3 ganger daglig, med en pH av 5-7,5. ;Detaljert beskrivelse av oppfinnelsen ;I de nedenstående spesifikke eksempler på munnpleiepreparater ifølge oppfinnelsen er alle mengder cg andeler basert på vekt dersom intet annet er angitt. Det samme gjelder for patentkravene. ;Eksempel 1 ;;<K>Blokkpolymer av ca. 80 vekt% polyoxyethylen og ca. 20 vekt% polyoxypropylen, idet polyoxypropylenradikalet har en molekylvekt av 3250, erholdt fra BASF Wyandotte Company. ;Climbazole blir blandet med Pluronid* inntil det er blitt homogent og klart, før den vandige-alkoholiske bærer inneholdende glycerol, smaksmiddel og natriumsaccharin tilsettes. sold under the trade name Tweerr<*> 20 which is also known as "Polysorbate 20" which is polyoxyethylene '(20)-sorbitan mono-laurate. Similar useful products are sold under similar designations, such as Tween 40, 60, 65 or 80, all of which are non-ionic surfactants in which the higher fatty acyl group is palmitoyl, stearoyl or oleyoyl and the number of moles of ethylene oxide per . molecule is approx. 20. Among these materials, however, polyoxyethylene sorbitan monolaurate is generally preferred. Polyoxyethylene (80) sorbitan monolaurate can be used instead of the aforementioned "Polysorbate 20". Other suitable nonionic surfactants include the mono- or diethanolamides of higher fatty acids with 10-18 carbon atoms in the acyl group, such as coco mcnoethanolamide, coco diethanolamide, lauric myristic diethanolamide, lauric monoethanolamide or combinations thereof. The oral care preparations produced according to the invention can be essentially paste-like, such as a toothpaste or a toothpaste. The carrier in such paste-like oral care preparations contains polishing material. Examples of polishing materials are water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, aluminum oxide, hydrated aluminum oxide, aluminum silicate, zirconium silicates, silicon dioxide bentonite, crystalline silicon dioxide with particles of sizes up to 5um, silica gel, complex amorphous alkali metal aluminum silicate, hydrated aluminum oxide, dicalcium phosphate or mixtures thereof. When visually clear gels are prepared, a polishing agent is colloidal silicon dioxide, such as that sold under the trade name Syloid®, such as Syloicr^ 72 or Syloi"d® 74, or under the trade name Santocel, such as SantoceP^ 100, or alkali metal- aluminum silicate complexes particularly useful because they have refractive indices close to the refractive indices of the gel-agent-liquid (including water and/or humectant) systems commonly used in dentifrices. ;The polishing material is generally present in an amount of 10-99% by weight of the oral care preparation. It is preferably present in an amount of 10-75% in a toothpaste. ;In a toothpaste, the liquid carrier comprises water and humectant typically in an amount of 10-90% by weight of the preparation. An essential component of the toothpaste and in toothpaste is 20-40% by weight of a non-ionic humectant including at least one of polyethylene glycol or polypropylene glycol to render the water insoluble Climba zole soluble in the aqueous carrier. Glycerol, sorbitol or mannitol can be used instead of part of the humectant, provided that the imidazole compound is soluble in polyoxyethylene or polyoxypropylene glycol. ;A geimiadei, such as natural or synthetic gums or gums or gum-like materials, typically Irish moss, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, gum tragacanth, polyvinylpyrrolidone, starch or hydroxypropylmethylcellulose, is usually present in toothpastes in an amount up to 1% by weight, preferably within the range 0.5-5% by weight. In a toothpaste or gel, the liquids and solids are used in such relative quantities that a cream-like or gelled mass is formed which can be extruded from a pressure container or from a collapsible tube of e.g. aluminum or lead. The oral care preparations prepared according to the invention may contain a synthetic, sufficiently water-soluble, organic, anionic or non-ionic surfactant that is not soap, in concentrations of 1-5% by weight to promote wetting, cleaning power and foaming at the mouth. In US Patent 4041149, such suitable anionic surfactants are described in column 4, lines 31-38, and such suitable nonionic surfactants are described in column 8, lines 30-68, and in column 9, lines 1-12. ;Oral care<p>the preparations produced according to the invention which contain the antibacterial agent, may optionally contain a fluorine-releasing compound, including inorganic fluoride salts, such as soluble alkali metal, alkaline earth metal or heavy metal salts, e.g. sodium fluoride, potassium fluoride, ammonium fluoride, calcium fluoride, a copper fluoride, such as monovalent copper fluoride, zinc fluoride, a stannous fluoride, such as tetravalent stannous fluoride or divalent stannous chlorofluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monoflucrphosphate, aluminum mono- or -difluorophosphate or fluorinated sodium calcium pyrophosphate. Alkali metal and stannous fluorides, such as sodium or divalent stannous fluorides, sodium monofluorophosphate or mixtures thereof, are preferred. The amount of the fluorine-releasing compound depends to some extent on the type of compound, its solubility and the type of oral care agent, but the amount must be a non-toxic amount. In a solid oral care preparation, such as a toothpaste or chewing gum, an amount of such a compound which will release a maximum of 1% by weight of fluorine in relation to the preparation is considered satisfactory. Any suitable minimum amount of such a compound can be used, but it is preferable to use enough of the compound so that 0.005-1, preferably approx. 0.1% fluoride ions will be emitted. For alkali metal fluorides and divalent stannous fluoride, this component is typically present in an amount of up to 2% by weight, based on the weight of the preparation, and preferably within the range of 0.05-1% by weight. For sodium monofluorophosphate, this component may be present in an amount up to 7.6% by weight, more typically approx. 0.76%. ;Various other materials can be incorporated into the oral care preparations produced according to the invention which do not adversely affect the properties of the preparations, such as sweeteners (e.g. saccharin, sucrose, lactose, maltose or sorbitol etc), flavoring oils (e.g. oils of spearmint, peppermint, wintergreen, sassafras, cloves, sage, eucalyptus, ir.erian, cinnamon, lemon or orange etc), coloring or whitening agents (e.g. titanium dioxide) or preservatives (e.g. sodium benzoate) etc. Smaller amounts of accumulated to 5% by weight, preferably 0.01-3% by weight, of these materials can be added to the oral care preparation. The oral care preparations produced by the present method can be easily produced using simple mixing methods from readily available components. However, it is of significant importance that the irtidazoyl compound is first mixed with the non-ionic component before it is added to the oral care agent carrier such as water. For example, a mouthwash or mouthwash can be prepared by first solubilizing the imidazole compound by emulsifying it in a non-ionic surfactant prior to addition to the aqueous or alcoholic-aqueous carrier. The other ingredients, such as flavoring agents or flavoring agents, etc., can be added to the aqueous carrier before or after the addition of the solubilized imidazole to the aqueous carrier. The toothpaste can be prepared by first mixing the imidazole compound with the humectant which is non-ionic, in which it is made soluble, and then adding the thickener, e.g. carboxymethyl cellulose to form a gel, followed by the addition of polishing agent, water and other ingredients. The order of addition of the various components can be varied, provided that the imidazole compound is first solubilized in the nonionic humectant before the water component is added. ;An oral care preparation prepared according to the invention, such as a mouthwash or a toothpaste, which contains 1-imidazoyl-1-(p-chloro-phenoxy)-3, 3-dimethyl-2-butanone as an antigingivitis agent in an amount which will effectively promote oral hygiene, is regularly applied to tooth enamel, preferably 1-3 times a day, with a pH of 5-7.5. ;Detailed description of the invention ;In the following specific examples of oral care preparations according to the invention, all amounts and proportions are based on weight if nothing else is stated. The same applies to patent claims. ;Example 1 ;;<K>Block polymer of approx. 80% by weight polyoxyethylene and approx. 20% by weight polyoxypropylene, the polyoxypropylene radical having a molecular weight of 3250, obtained from BASF Wyandotte Company. ;Climbazole is mixed with Pluronid* until it has become homogeneous and clear, before the aqueous-alcoholic carrier containing glycerol, flavoring agent and sodium saccharin is added.
Det erholdte produkt er effektivt istand til å bekjempe tannkjøttbetennelse og til å behandle periodontitt og er et enkelt middel for å forbedre munnhygienen når det anvendes regelmessig med 1-3 tilførsler daglig til munnhulen. The product obtained is effectively able to combat gingivitis and to treat periodontitis and is a simple means of improving oral hygiene when used regularly with 1-3 applications daily to the oral cavity.
Den overraskende overlegne antigingivittaktivitet for dette produkt er underbygget i tabell 1 for et munnskyllevann ifølge eksempel 1 anvendt som forsøksoppløsning. Dette produkt oppviser også antibakterielle egenskaper mot Bacteroides assaccharolyticus og B. gingivalis. The surprisingly superior antigingivitis activity of this product is substantiated in Table 1 for a mouthwash according to example 1 used as a test solution. This product also exhibits antibacterial properties against Bacteroides assaccharolyticus and B. gingivalis.
Eksempel 2 Example 2
1H(OCH2CH2)rOH hvori n er et tall mellom 10 og 14, fortrinnsvis fra 12,5 til 14, og hvor molekylvekten er 570-630 1H(OCH2CH2)rOH where n is a number between 10 and 14, preferably from 12.5 to 14, and where the molecular weight is 570-630
<2>kolloidalt siliciumdioxyd <2>colloidal silicon dioxide
<3>natriumaluminosilikat (siliciumdioxyd med 1% kombinert aluminiumoxyd) <3>sodium aluminosilicate (silicon dioxide with 1% combined aluminum oxide)
Climbazole forhåndsblandes med polyethylenglycolen før carboxymethylcellulosen tilsettes, hvorved en gel dannes. Til denne gel blir under omrøring Syloi "Zeo", natriumlaurylsulfat, smaksmiddel, vann, benzoat og saccharin tilsatt. Benzoatet og saccharinet kan oppløses i vannet før de blandes med resten av bestanddelene. På lignende måte kan "Zeo", smaksmiddel og natriumlaurylsulfat blandes med hverandre på forhånd før de tilsettes, til gelen. Climbazole is premixed with the polyethylene glycol before the carboxymethylcellulose is added, whereby a gel is formed. Syloi "Zeo", sodium lauryl sulphate, flavouring, water, benzoate and saccharin are added to this gel while stirring. The benzoate and saccharin can be dissolved in the water before mixing with the rest of the ingredients. Similarly, the "Zeo", flavoring agent and sodium lauryl sulfate can be premixed with each other before being added to the gel.
Dette produkt oppviser også lignende gode antimikrobielle og antigingivittegenskaper. This product also exhibits similarly good antimicrobial and antigingivitis properties.
Andre vanlige bestanddeler kan anvendes som erstatning eller tilsettes, som beskrevet ovenfor. For eksempel kan hydratisert aluminiumoxyd eller vannuoppløselig metafosfat eller dikalsiumfosfatdihydrat eller andre pcleringsmidler anvendes istedenfor alkalimetållaluminosilikatet ("Zeo") eller det kolloidale siliciumdioxyd (Syloi helt eller delvis. På lignende måte kan andre ikke-ioniske overflateaktive midler anvendes istedenfor blokkpolymeren av propylenoxyd og ethylenoxyd (PluronicH, som f.eks. poly-oxyethylenhexitan-monohøyere-fettsyreesterne. Other common ingredients can be used as substitutes or added, as described above. For example, hydrated aluminum oxide or water-insoluble metaphosphate or dicalcium phosphate dihydrate or other clarification agents can be used instead of the alkali metal aluminosilicate ("Zeo") or the colloidal silicon dioxide (Syloi) in whole or in part. Similarly, other nonionic surfactants can be used instead of the block polymer of propylene oxide and ethylene oxide (PluronicH , such as the polyoxyethylenehexitan monohigher fatty acid esters.
Claims (5)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US44240582A | 1982-11-17 | 1982-11-17 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO834201L NO834201L (en) | 1984-05-18 |
NO171094B true NO171094B (en) | 1992-10-19 |
NO171094C NO171094C (en) | 1993-01-27 |
Family
ID=23756687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO834201A NO171094C (en) | 1982-11-17 | 1983-11-16 | PROCEDURE FOR PREPARING AN ORAL CARE PREPARATION |
Country Status (27)
Country | Link |
---|---|
JP (1) | JPS59108717A (en) |
AT (1) | AT388661B (en) |
AU (1) | AU550144B2 (en) |
BE (1) | BE898245A (en) |
BR (1) | BR8306276A (en) |
CA (1) | CA1227139A (en) |
CH (1) | CH656528A5 (en) |
DE (1) | DE3340878C2 (en) |
ES (1) | ES8604775A1 (en) |
FI (1) | FI78832C (en) |
FR (1) | FR2535970B1 (en) |
GB (2) | GB8330671D0 (en) |
GR (1) | GR79100B (en) |
HK (2) | HK71589A (en) |
IE (1) | IE56280B1 (en) |
IT (1) | IT1206160B (en) |
MX (1) | MX157553A (en) |
MY (1) | MY8700950A (en) |
NL (1) | NL8303962A (en) |
NO (1) | NO171094C (en) |
NZ (1) | NZ206200A (en) |
PH (1) | PH19311A (en) |
PT (1) | PT77656A (en) |
SE (1) | SE459845B (en) |
SG (1) | SG40089G (en) |
ZA (1) | ZA838185B (en) |
ZW (1) | ZW24183A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017084826A1 (en) * | 2015-11-17 | 2017-05-26 | Unilever Plc | Climbazole microcapsule and hair care composition comprising surfactant and climbazole |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2105490C3 (en) * | 1971-02-05 | 1979-06-13 | Bayer Ag, 5090 Leverkusen | 1-imidazolyl ketone derivatives |
US3903287A (en) * | 1971-02-05 | 1975-09-02 | Bayer Ag | Imidazolyl ketones for treating mycotic infections |
DE2430039C2 (en) * | 1974-06-22 | 1983-11-10 | Bayer Ag, 5090 Leverkusen | Climbazole in cosmetic products |
-
1983
- 1983-11-02 ZA ZA838185A patent/ZA838185B/en unknown
- 1983-11-08 NZ NZ206200A patent/NZ206200A/en unknown
- 1983-11-08 ZW ZW241/83A patent/ZW24183A1/en unknown
- 1983-11-08 MX MX199333A patent/MX157553A/en unknown
- 1983-11-11 DE DE3340878A patent/DE3340878C2/en not_active Expired - Fee Related
- 1983-11-14 PT PT77656A patent/PT77656A/en unknown
- 1983-11-15 AU AU21368/83A patent/AU550144B2/en not_active Ceased
- 1983-11-16 AT AT0403183A patent/AT388661B/en not_active IP Right Cessation
- 1983-11-16 SE SE8306305A patent/SE459845B/en not_active IP Right Cessation
- 1983-11-16 ES ES527310A patent/ES8604775A1/en not_active Expired
- 1983-11-16 FI FI834194A patent/FI78832C/en not_active IP Right Cessation
- 1983-11-16 PH PH29847A patent/PH19311A/en unknown
- 1983-11-16 NO NO834201A patent/NO171094C/en unknown
- 1983-11-16 FR FR8318224A patent/FR2535970B1/en not_active Expired
- 1983-11-16 BR BR8306276A patent/BR8306276A/en unknown
- 1983-11-17 GB GB838330671A patent/GB8330671D0/en active Pending
- 1983-11-17 IT IT8349359A patent/IT1206160B/en active
- 1983-11-17 GR GR73010A patent/GR79100B/el unknown
- 1983-11-17 IE IE2693/83A patent/IE56280B1/en not_active IP Right Cessation
- 1983-11-17 CA CA000441362A patent/CA1227139A/en not_active Expired
- 1983-11-17 CH CH6187/83A patent/CH656528A5/en not_active IP Right Cessation
- 1983-11-17 NL NL8303962A patent/NL8303962A/en not_active Application Discontinuation
- 1983-11-17 JP JP58217072A patent/JPS59108717A/en active Granted
- 1983-11-17 GB GB08330727A patent/GB2130089B/en not_active Expired
- 1983-11-17 BE BE0/211887A patent/BE898245A/en not_active IP Right Cessation
-
1987
- 1987-12-30 MY MY950/87A patent/MY8700950A/en unknown
-
1989
- 1989-07-01 SG SG400/89A patent/SG40089G/en unknown
- 1989-09-07 HK HK715/89A patent/HK71589A/en unknown
-
1991
- 1991-07-18 HK HK544/91A patent/HK54491A/en unknown
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