CA2099920C - Modified chlorhexidine-adduct - Google Patents
Modified chlorhexidine-adductInfo
- Publication number
- CA2099920C CA2099920C CA002099920A CA2099920A CA2099920C CA 2099920 C CA2099920 C CA 2099920C CA 002099920 A CA002099920 A CA 002099920A CA 2099920 A CA2099920 A CA 2099920A CA 2099920 C CA2099920 C CA 2099920C
- Authority
- CA
- Canada
- Prior art keywords
- adduct
- chlorhexidine
- tin
- dental
- plaque
- Prior art date
- 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.)
- Expired - Fee Related
Links
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960003260 chlorhexidine Drugs 0.000 claims abstract description 13
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910000040 hydrogen fluoride Inorganic materials 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 229910001868 water Inorganic materials 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 208000002925 dental caries Diseases 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 7
- ANOBYBYXJXCGBS-UHFFFAOYSA-L stannous fluoride Chemical compound F[Sn]F ANOBYBYXJXCGBS-UHFFFAOYSA-L 0.000 claims description 7
- 229960002799 stannous fluoride Drugs 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 12
- 241000194019 Streptococcus mutans Species 0.000 abstract description 6
- GEAOJWKXHMGANA-UHFFFAOYSA-N $l^{1}-stannane Chemical compound [SnH] GEAOJWKXHMGANA-UHFFFAOYSA-N 0.000 abstract 1
- 239000000463 material Substances 0.000 description 15
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 11
- 239000005548 dental material Substances 0.000 description 11
- 238000011049 filling Methods 0.000 description 10
- 239000003955 fissure sealant Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 9
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 8
- 230000002882 anti-plaque Effects 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000069 prophylactic effect Effects 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 208000027418 Wounds and injury Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 244000005700 microbiome Species 0.000 description 4
- 235000010585 Ammi visnaga Nutrition 0.000 description 3
- 244000153158 Ammi visnaga Species 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000628997 Flos Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical class O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000004568 cement Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 150000002500 ions Chemical group 0.000 description 3
- 230000005012 migration Effects 0.000 description 3
- 238000013508 migration Methods 0.000 description 3
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 3
- 208000028169 periodontal disease Diseases 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- -1 tin (II) ions Chemical class 0.000 description 3
- VNQXSTWCDUXYEZ-UHFFFAOYSA-N 1,7,7-trimethylbicyclo[2.2.1]heptane-2,3-dione Chemical compound C1CC2(C)C(=O)C(=O)C1C2(C)C VNQXSTWCDUXYEZ-UHFFFAOYSA-N 0.000 description 2
- HWSSEYVMGDIFMH-UHFFFAOYSA-N 2-[2-[2-(2-methylprop-2-enoyloxy)ethoxy]ethoxy]ethyl 2-methylprop-2-enoate Chemical compound CC(=C)C(=O)OCCOCCOCCOC(=O)C(C)=C HWSSEYVMGDIFMH-UHFFFAOYSA-N 0.000 description 2
- IXXLKTZOCSRXEM-UHFFFAOYSA-N 3-(n-methylanilino)propanenitrile Chemical compound N#CCCN(C)C1=CC=CC=C1 IXXLKTZOCSRXEM-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 241000222122 Candida albicans Species 0.000 description 2
- 208000002064 Dental Plaque Diseases 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- 206010041662 Splinter Diseases 0.000 description 2
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940095731 candida albicans Drugs 0.000 description 2
- 229940112822 chewing gum Drugs 0.000 description 2
- 235000015218 chewing gum Nutrition 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 210000003298 dental enamel Anatomy 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- MKVYSRNJLWTVIK-UHFFFAOYSA-N ethyl carbamate;2-methylprop-2-enoic acid Chemical compound CCOC(N)=O.CC(=C)C(O)=O.CC(=C)C(O)=O MKVYSRNJLWTVIK-UHFFFAOYSA-N 0.000 description 2
- 210000004195 gingiva Anatomy 0.000 description 2
- 208000007565 gingivitis Diseases 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 210000003739 neck Anatomy 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 230000007505 plaque formation Effects 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 229910052682 stishovite Inorganic materials 0.000 description 2
- 229910001432 tin ion Inorganic materials 0.000 description 2
- 229910052905 tridymite Inorganic materials 0.000 description 2
- MFEWNFVBWPABCX-UHFFFAOYSA-N 1,1,2,2-tetraphenylethane-1,2-diol Chemical compound C=1C=CC=CC=1C(C(O)(C=1C=CC=CC=1)C=1C=CC=CC=1)(O)C1=CC=CC=C1 MFEWNFVBWPABCX-UHFFFAOYSA-N 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 241000870659 Crassula perfoliata var. minor Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- AMFGWXWBFGVCKG-UHFFFAOYSA-N Panavia opaque Chemical compound C1=CC(OCC(O)COC(=O)C(=C)C)=CC=C1C(C)(C)C1=CC=C(OCC(O)COC(=O)C(C)=C)C=C1 AMFGWXWBFGVCKG-UHFFFAOYSA-N 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 206010039424 Salivary hypersecretion Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- 230000000675 anti-caries Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- ISAOCJYIOMOJEB-UHFFFAOYSA-N benzoin Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=CC=C1 ISAOCJYIOMOJEB-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000001013 cariogenic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000005115 demineralization Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003722 gum benzoin Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011256 inorganic filler Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000000025 natural resin Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- ZVVSSOQAYNYNPP-UHFFFAOYSA-N olaflur Chemical compound F.F.CCCCCCCCCCCCCCCCCCN(CCO)CCCN(CCO)CCO ZVVSSOQAYNYNPP-UHFFFAOYSA-N 0.000 description 1
- 229960001245 olaflur Drugs 0.000 description 1
- 239000012766 organic filler Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 239000000565 sealant Substances 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 239000000606 toothpaste Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/43—Guanidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
- C07C279/265—X and Y being nitrogen atoms, i.e. biguanides containing two or more biguanide groups
Abstract
A chlorhexidine adduct is described, which comprises one molecule of chlorhexidine with three molecules of hydrogen fluoride and one molecule of hydrogen tin trifluoride. The adduct displays a high antibacterial effectiveness against Streptococcus mutans even in very low concentrations.
Description
2~920 The invention relates to a chlnrh~Y~r~inf~ adduct which can be used as an antiseptic and in particular as an antLseptic in dentistry as well as a therapeutic and prophylactic anti-plaque agent.
5 In the attempt to inhibit or completely stop the f ormation of plaque and therefore also of caries, the effectiveness of substances with antibacterial properties such as chlorinated phenols, formaldehyde and quaternary ammonium compounds has been tested in the past. ~owever, these c, ~1~ have not been 10 introduced into practlce in view of their toxicity and their limited action spectrum.
The most effective anti-plaque agent at present is chlorhr~Y~-lin~
(1,6-bis-(N5-p-chlorophenyl-N'-diguanidino)-hexane) whichisused 15 particularly in the form of the water-soluble digluconate and also as the sparingly soluble diacetate and dihydrochloride (cf.
A.Scheie in J. Dent. Res. 68, 1609 (1989) and P. Gjermo in J.
Dent. Res. 68, 1602 (1989) ) .
20 Apart from these r~h1r~rh~ 1i n1~ compounds, chlorh~Yi~i n~
dihydrofluoride is also known which, according to DE-OS 21 58 150, is used as an antiseptic agent in transparent tooth gels.
Moreover, a mixture of ~hl~-rhr~Yidine, amine fluoride and tin 25 difluoride is known from I. Ostela and J. Tenovuo in Scand. J.
Dent. Res. 98, 1 (1990). This mixture can be used in tooth gels as a bactericide against cariogenic bacteria.
It has been shown that by using chlorhexidine as a 3 0 chemotherapeutic, bacteria of the type Streptococcus mutans can be countered effectively. Bacteria of this type play an essential role in the formation of caries on human teeth. It is therefore assumed that by reducing their quantity on the surface of teeth, the formation of caries can be effectively prevented (cf. I.
ostela and J. Tenovuo in Scand. J. Dent. Res. 98, 1 ( 1990) ) . ~t~
... . . . . ... , . , . . , ~
2~9~920 ~ - 2 -The bactericidal action which -hlqrhf~Y;cl;n~ exerts against bacteria of the type Strepto~ occl~ mutans iY, however, severely weakened if it is used in low concentrations. Even f-hl~rh~Y;~lln~
is, therefore, sub~ect to significant limitations in practical applications where reducing the amount of tooth plaque is important, which otherwise can lead to the formation of parodontosis and caries. Furth~ , the use of chlr)rheYi~lin~
in higher concentrations can result in undesirable discolorations of the tongue, teeth, prostheses and fillings (cf. L. Flqtra, P.
G~ermo, G. Rolla and J. Waerhaug in Scand. J. Dent. Res. 79, 119 ( 1971 ) ) .
Tin ions show a significant anti-caries action and a plaque-inhibiting effect. Firstly, the metabolism of the microorganisms 15 present in the plaque is disrupted (see e.g. J.E. Ellingsen, B.
Svatun and G. Rolla, Acta Odontol. Scand. 38, 219 (1980) and N.
Tinanoff, J.M. Brady and A. Gross, Caries Res. 10, 415 (1976)), and, secondly, tin (II) ions are deposited on the surface of the tooth and form acid-resistant precipitates there, together with 20 fluoride, calcium and phosphate ions (see e.g. J.E. Ellingsen, Scand. J. Dent. Res. 94, 229 (1986) and J.E. Ellingsen and G.
Rolla, Scand. J. Dent . Res . 95, 281 ( 1987 ) ) .
It is therefore the ob~ect of the invention to provide a 25 chlorh~Yi~linl~ adduct which, as an anti-plaque agent, effectively counters the formation and growth of tooth plaque even in very low concentrations, which can desensitize sensitive tooth necks and moreover which, through fluoride release, is capable of protecting the tooth enamel against fi~ n~r;~ atiOn, 30 particularly demineralisation by acids.
This ob~ect is surprisingly achieved by the ~hl~rh~x~in~ adduct according to claim 1 and the process for its production according to claims 2, 3 and 4 and its use according to claims 5 and 6.
` ~ 2~3~92~
- 2a -Preferred embodiments of the invention will now be described, with reference to the accompanying drawings, in which:
Fig 1 is an IR spectrum of the chlorhexidine adduct of the present invention;
Fig 2 is a secondary ions mass spectrometry of Example 3;
Fig 3 is a graph showing f luoride release over time according to Examples 4 and 5; and Fig 4 is a graph showing chlorhexidine release over time c~cording to Exa~l^e 4 .In~l 5.
/
2~9~920 .
The chlnrh~ n~ adduct according to the inventLon is a compound of the following formula:
Cl-~3 -NX-C-~-C~ - ( C~2 ) 6-~H-C-~H-C-~ 3 -C1 ~H NE~ NH ~I
3 ~IF ~IsnFs or its hydrates.
The adduct displays the IR spectrum according to Figure 1. The exact molecular structure of the adduct according to the invention i8 not known. ~3asically, it is possible that the adduct accordlng to the invention consists of electrically neutral molecules or is present in the form of ion5 and hence as a salt.
The adduct according to the invention is produced by reacting a chlr,rh~i~lln~ salt (preferably rhlnrhi~ n.o 1;qll~rnn~te), tin difluoride and hydrogen fluoride in a molar ratio of 1: 1 to 4 4 to 8 in a mixture of 3: l parts by volume ethanol/water as solvent and separating the precipitate formed.
The rhlnrh~ n~ according to the invention is preferably prepared by carrying out the reactLon at room temperature with a chlnrh~Yi~in~ salt to tin ~l~fll~nri~l~ to ILYd~UYI::~ fluoride molar ratio of 1: 4: 6. The yields thus obt~n~hl~ are 90 to almost 100% .
Increased temperatures are dlsadvantageous when carrying out the productlon process since they promote the formation of mi~ed 3 o products with a lower tin f luoride content .
A reaction time of 24 hours is usually sufficient to achieve a complete reaction. The reaction time can, however, vary depending on the reaction parameters selected. The best-suited reaction 2Q9~920 time for the case in question can, however, be ~lPtPrminPfl easily by routine Plrrl~r; ts.
The chlt~rhR~ inP adduct formed by the reaction prP~l~ ;n;-ntly as S precipitate Ls removed and purified, preferably by filtration and subsequent washing with water and acetone. By working-up of the mother liquors, further chlorhexidine adduct can be obtained, so that overall yields of 90 to almost 10096 are obtainable. The purified product is then dried in a conventional way and 10 afterwards exists in the form of hydrates with varying levels of water, dPr~n~lin~ on the degree of drying.
Because of its strong antibacterial action, the chlorhPY;~linP
adduct according to the invention can be used as a therapeutic 15 or prophylactic anti-plaque agent. In doing so, it prevents the formation of plaque and inhibits the growth of films already present on the tooth. Diseases which are caused by the presence of plaque, such as parodontosis, caries and gingivitis, are therefore able to be tackled effectively with the chlorhP~ nP
20 adduct according to the invention. Furthermore, it can contribute to the desensitizing of sensitive tooth necks. It is preferably used in dental materials, such as tooth v~rn;RhP~, fissure sealants, prophylactic pastes, mouthwashes, toothpicks, dental floss, dental chewing-gum, wound dressings, dental creams, 2~ gingiva ~r~;nPrS, disinfectants for protheses and impression materials, drying agents, under-f illing materials, cements, filling materials, adhesives and endodontic materLals . The adduct according to the invention can be deposited on a solid substrate, such as a toothpick or dental floss, or incorporated into dental materials, such as provisional filling materials and fissure sealants .
Of particular advantage is the incorporation of the adduct according to the invention in dental materials which are to remain in the oral cavity for a limited period of time, such as provisional filling materials, wound dressings, impression materials and t-o~rnr~ry cements. If the adduct according to the invention is incorporated for example into a provisional filling material, one obtains, after its removal, a germ-free cavity into 5 which the final filling can immediately afterwards be placed.
Since the chlnrh~ ;; n-~ adduct is only very slightly soluble in common solvents, it is preferably incorporated into the said dental materials as a solid. It is added to the dental materials in quantities of 0.1 to 20 wt.%, preferably 1 to 10 wt.96 and particularly preferably 3 to 7 wt.g~, relative to the total weight of the material. Examples of suitable dental materials are those which contain 10 to 95 wt. 9s poly ~ ~hl e organic binder, 5 to 90 wt.96 inorganic and/or organic fillers and 0.01 to 5 wt.%
15 catalysts, relative to the weight of the total material.
Furthermore, solutions containing 0.03 to 0.001 wt.96 of the adduct according to the invention can be used. Suitable as solvents are e.g. water, ethanol, acetone, ethyl acetate, 20 triethylene glycol dimethacrylate and ~ nef~;nl dimethacrylate.
Further, synthetic or natural resins can be used which are soluble in common solvents and become hard af ter evaporation of the solvent. Examples for such resins are shellac, benzoin resin, 25 polyvinyl pyrrolidone and colophony.
A further preferred application of ~he chlnrh~ i n~ adduct is that as a therapeutic or prophylactic anti-plaque agent. It prevents the formation of plaque and inhibits the growth of plaque already present. Diseases which are caused by the presence 30 of plaque, e.g. parodontosis, primary and secondary caries and gingivitis, can therefore be combatted effectively with the chlorhexidine adduct according to the invention.
As regards its bactericidal effectiveness, the nhlnrh~Yirl;nf~
adduct according to the invention is fully comparable in a _ _ _ _ _ _ _ _ _ _ _ _ . . , . . .... . . . . . . _ . .. . . . ..... _ _ ... . .
2~9~2~
concentration of 0.03 wt.96 with ~hlnrhf~ nP, which at present is regarded as the most effective anti-plaque agent.
Surprisingly, however, the effectiveness of chl~rh~YI~linP is significantly surpassed if both are used in concentrations less 5 than or equal to 0 . 01 wt . 96 . In this concentration range, the chlnrhPY; ~1 i nQ adduct according to the invention is even clearly superior to tin difluoride, a compound known to have very good bactericidal properties.
10 The superiority of the adduct according to the invention especially in low concentrations is of particular significance for practical applications. For, as a result of the rPrr-npnt salivation in the oral cavity, the active ingredients used are continuously diluted. An actlve ingredient, such as the 15 chlorhP~ inP adduct according to the invention, which shows a strong bactericidal effect even in low concentrations, is theref ore of particular advantage .
Finally, the high fluorine content of the adduct ac~nrlin~ to the 20 invention means that it can effect h~r~iPnin~ of the tooth enamel through fluoridization and therefore can also efectively protect against the formation of caries in this respect. The adduct according to the invention further shows the aforementioned effect of tin ions.
The adduct according to the invention can be worked in or applied on dental materials such as inter alia the aorementioned filling compositions, dental v~rni~hP~, fissure sealants, prophylactic pastes, tooth-picks, dental floss, dental chewing-gum, wound 30 dressings, dental creams, gingiva trainers, disinfectants for protheses and impression materials, drying agents, under-filling materials, cements, filling materials, adhesives and endodontic materials, or applied on the teeth in the form of many different dental treatment agents, such as toothpastes, tooth gels, tooth v~rni~hP~ or mouth rinses.
_ _ _ _ .
2~ D
The invention is described in more detail in the following examples .
Example 1 To produce the chlorh~Y;r1;n~ adduct according to the invention, 480 ml ethanol/water (3:1) were introduced first and 12.6 g (0.08 mole) tin difluoride and 6 g of a 40 % HF solution (0.12 mole) dissolved therein. 85 ml (corresponding to 90 g) (0.02 mole) of an aqueous 20% chlorh~Y;~lin~ digluconate solution were added dropwise with stirring within an hour. After a further 5 hours stirring, the precipitate formed was filtered off and washed three times with 50 ml ethanol/water (3:1). Further product crystallised out from the mother liquor within a week. Drying of the precipitate obtained was carried out in the drying cupboard at 50C. The yield of adduct was almost quantitative.
The IR spectrum (RBr pressed disk) is reproduced in Figure 1.
The ~lementary analysis shows that the product is rhl~rh~Y~in~
trihydrofluoride-hydrogen tin trifluoride with 2 moles crystal water.
C22H3ONIocl2 3 HF ~ HSnF3 ~ 2 H20 ~IW = 778 . 2 Elementary analysis:
found theoretical C 34.48% 33.96%
H 4.56% ~.40%
N 18 . 02% 18 . 00%
Cl 9 . 06% 9 . 11%
F 14 . 58% 14 . 65%
Sn 14 . 45% 15 . 259 H2O ) 4 . 84% 4 . 63%
}i20 content de~rmi nl~d by the ~arl Fischer method (Note: The theoretical value of 15 . 2596 for tin is not achieved in the elementary analysig since chlnrh~ nl~
hexahydrof l i~nr~ forms as a by-product during the synthesis in a yield of about 59~. The value for tin therefore falls, whilst a higher value is measured for carbon. ) Solubility:
Water 0 . 03 wt . 96 Ethanol 0 . 02 wt . 96 l~xample 2 The antibacterial effectiveness of the t-hlclrh~r;flinP adduct 15 according to the invention was demonstrated in the agar-diffusion test with StrePtoCOcCuS mutans.
For this, culture suspensions of Stre~tococcus mutans were introduced in liquid yeast-extract-dextrose-agar. After solidification of the agar plates, a basin of 10 mm diameter was cut out. Into this were poured 0.1 ml of the respective test 20 solution. The samples were prepared in duplicate in each case and the diameters of the zones of inhibition were measured after 24-hour incubation at 37C. The results of these tests are set out in the following Table I.
20~9~
g Table I
Inl~bition 2 one diameters Concentration Solution A Solution B SQlution C
0 . 03 wt. % 17 mm 16 mm 20 mm O . 01 wt. 96 13 mm 15 mm ll mm 5 0 . 003 wt . 96 ll mm 11 mm 10 mm no effectiveness Solution A: Aqueous solution of chlorh~Y;~;n~ digluconate Solution B: Aqueous solution of the chlorhf~Y;~;n~ adduct according to the invention Solution C: Aqueous solution of tin dif luoride The test result show that at a concentration of 0 . 03 wt. 96 the antibacterial effectiveness of the chlnrh~Y;~;;n~ adduct according to the invention against Streptococcus mutans i5 comparable with that of ~hlorheY;ci;n~ digluconate, whilst tin difluoride displays an even stronger action at this concentration. With increasing dilution, however, the effectiveness of the known compounds falls sharply, in the case of tin rl;fltlnri~ at a concentration of O . O 0 3 wt . 9~ even to the extent that an anti-bacterial ef f ect can no longer be detected. In contrast to this, the antibacterial effectiveness of the adduct according to the invention is still very high even at concentrations of 0 . Ol to 0 . 003 wt. 96 . Its superiority especially at low concentrations thus makes it a very ef f ective anti-plaque agent .
EYam~le 3 A dental material as described in Example 4 was deposited in a layer of ca. 2 mm on the surface of an absolutely plane-parallel, tin-free hydroxyl-apatite testpiece and polymerised for 40 _ _ . , , . . _ .. _ .. . . _ _ _ _ . .
~992~
seconds with the Heliomat~ (light apparatus from Vivadent).
Afterwards, the thus-coated testpiece was stored for 12 hours at 37C in distilled water. The poly ~ on layer was then removed with microscopic control and the tin content on the 5 hydroxyl apatite surface was analyzed by means of SI~IS (secondary ions mass spectrometry). This analysis process is described in Caries Res. 20, 419 (1986).
~he result obtained is depicted in Figure 2 and shows that a considerable portlon of the tin present in the dental material 10 was deposited on the surface of the hydroxyl apatite.
l~amPle 4 A light-curing fissure sealant contains the following ~ ~ntS:
56 . 08 wt. % Bis-phenol A-glycidyl methacrylate (Bis-Gl~A) 36 .1 wt. % Triethylene glycol dimethacrylate 0 . 45 wt . % Cyanoethylmethyl aniline 0 . 25 wt. % DL-camphor quinone 2.1 wt.% TiO2 0 . 02 wt. % 2, 6-di-tert. -butyl-p-cresol 5 . 0 wt . % Chlorh~ ~ i nf~ adduct The light-curable fissure sealant was obtained by mixing all the components. This was applied with a paint-brush onto the fissures of a molar and cured for 20 sec with the Heliolux' light-curing apparatus from Vivadent/Liechtenstein. The fissures were sealed 25 p-~r---nf-ntly in this way and, through the fluoride release of the chlorhexidine adduct incorporated in the sealant, excellent caries protection was obtained in the occlusal region.
By ;l~lmisring 1 to 5 wt.% of the chl~-rh~Y;-lin~ adduct to the fissure sealant basic formulation, no reduction in the degree of through-hardening was observed, as the following values for .
2Qg9~20 Vickers hardness show:
HV 0 . 5 Fissure sealant without ~h7nrh~ in-~ adduct 188 MPa Fissure sealant + 1% chlnrh~ ;n~ adduct 203 MPa Fissure sealant + 39~ ~hlorh~ in~ adduct 211 NPa Fissure sealant + 5~ chlnrhf~riflin~o adduct 184 ~Pa To demonstrate the chlnrh.oYi-linf~ and fluoride migration, 10 testpieces each with a diameter of 50 mm and a height of 0 . 5 mm were stored in dist. water at 37C. The concentration of fluo:ride ions was det~rmin~d using a fluoro-electrode, and the chlnrh~ 1 i n~ concentration was measured by means of W-10 spectroscopy. The results are set out below in Table II.
Table II
Cumulative fluoride and chlorh~yi~linf~ release ~igration time Fluoride Chlnrh~; ~i i n~
[days] release release [ llm/cm2] [ ,ug/cm2]
1.26 4.30 2 1.97 5.41 3 2.61 5.96 4 3.13 6.36 7 4.57 7.11 5 . 77 8 . 37 17 8 . 01 9 . 07 24 9 . 83 9 . 77 11 . 21 10 . 37 44 13 . 87 10 . 93 86 18 . 49 11 . 01 149 22 . 91 11 . og ` ~Dg~920 The results are represented graphically in Figures 3 and 4.
Examl~le 5 A light-curing dental plastic with relatively high water absorption and theref ore high active ingredient release ( e . g .
5 suitable as provisional filling material or as a wound dressing) has the following composition:
41. 4 wt . % polyester urethane dimethacrylate 0 . 25 wt. % cyanoethylmethyl aniline 0 .15 wt . % DL-camphor quinone 0 . 02 wt . % 2, 6-di-tert . -butyl-p-cresol 33 . 25 wt. % splinter polymerisate l9 . 93 wt. % finely-dispersed silanised SiO2 5 . 0 wt . % chlnrh~ i n~ adduct The splinter polymerisate consists of:
lS 59.4 % urethane dimethacrylate 40 % finely dispersed silanised SiO2 0 . 6 % benzpinacol These c~ ts are mixed together and polymerised at 120C. The filled polymerisate is ground to a polymer powder. The _~huux 20 finely-dispersed silanised SiOz is Aerosil~ OX 50 from Degusaa AG .
A light-curing dental material was obtained by mixing all the ,- ,r.n~ntS.
The water absorption of dental filling composites normally lies 25 in the region of 1 wt. ~ . However, this material shows a water absorption in the region of 3 wt.% (3 weeks EIzO storage at 37C).
Chlnrh~ r1~nf~ and fluoride migration:
. _ _ _ _ 2 ~
The cumulatlve fluoride and chlnrh~xl~lin~ release is 2,, ri~ed in the following table III.
Table III
5 ~ligration time Fluoride Chlorhexidine [ days ] release release [ llm/cm2 ] [ llm/cm2 ]
1.67 10.4 2 2.64 16.3 3 3.52 21.?
4 4 . 29 26 . 5 7 5.64 32.1 6 . 87 37 . 3 17 8.97 43.5 24 10 . 72 49 . 3 11.92 53.5 44 14 . 02 59 . 8 86 17.38 67.3 149 19 . 90 76 . 8 20 The results are represented graphically in Figures 3 and 4.
Microbioloqical action As the migration ~er; Ls show, signif icant quantities of fluoride and chlorh~xi-1~nf~ are released from this dental material, so that even in this combination a suf f icient 25 inhibition of the growth of microorganisms is to be expected.
Since not all microorganisms react equally on released active ingredients, investigations were conducted using the following microbes .
,9.g~
.
Gram-positive bacteria: Streptococcus mutans Staphylococcus aureus Gram-negative bacteria: Pæ~lt~t i~.C auruginOsa Escherichia coli Fun us: Candida albicans 10 g Testpieces (d = 10 mm, h = 2 mm) were introduced into the moist microorganism culture& at 37C over a period of 24 hours and then 15 the zone of inhibition was dett~rmint~
Zone of inhibition diameter [ mm ]
20 Streptococcus mutans 13 Staphylococcus aureus 14 Pseudomonas auruginosa 16 Escherichia coli 14 25 Candida albicans 10 (no effect) With the exception of Candida i~lhit.~n~t, a clear inhibition of growth in these various microorganlsms is detectable.
5 In the attempt to inhibit or completely stop the f ormation of plaque and therefore also of caries, the effectiveness of substances with antibacterial properties such as chlorinated phenols, formaldehyde and quaternary ammonium compounds has been tested in the past. ~owever, these c, ~1~ have not been 10 introduced into practlce in view of their toxicity and their limited action spectrum.
The most effective anti-plaque agent at present is chlorhr~Y~-lin~
(1,6-bis-(N5-p-chlorophenyl-N'-diguanidino)-hexane) whichisused 15 particularly in the form of the water-soluble digluconate and also as the sparingly soluble diacetate and dihydrochloride (cf.
A.Scheie in J. Dent. Res. 68, 1609 (1989) and P. Gjermo in J.
Dent. Res. 68, 1602 (1989) ) .
20 Apart from these r~h1r~rh~ 1i n1~ compounds, chlorh~Yi~i n~
dihydrofluoride is also known which, according to DE-OS 21 58 150, is used as an antiseptic agent in transparent tooth gels.
Moreover, a mixture of ~hl~-rhr~Yidine, amine fluoride and tin 25 difluoride is known from I. Ostela and J. Tenovuo in Scand. J.
Dent. Res. 98, 1 (1990). This mixture can be used in tooth gels as a bactericide against cariogenic bacteria.
It has been shown that by using chlorhexidine as a 3 0 chemotherapeutic, bacteria of the type Streptococcus mutans can be countered effectively. Bacteria of this type play an essential role in the formation of caries on human teeth. It is therefore assumed that by reducing their quantity on the surface of teeth, the formation of caries can be effectively prevented (cf. I.
ostela and J. Tenovuo in Scand. J. Dent. Res. 98, 1 ( 1990) ) . ~t~
... . . . . ... , . , . . , ~
2~9~920 ~ - 2 -The bactericidal action which -hlqrhf~Y;cl;n~ exerts against bacteria of the type Strepto~ occl~ mutans iY, however, severely weakened if it is used in low concentrations. Even f-hl~rh~Y;~lln~
is, therefore, sub~ect to significant limitations in practical applications where reducing the amount of tooth plaque is important, which otherwise can lead to the formation of parodontosis and caries. Furth~ , the use of chlr)rheYi~lin~
in higher concentrations can result in undesirable discolorations of the tongue, teeth, prostheses and fillings (cf. L. Flqtra, P.
G~ermo, G. Rolla and J. Waerhaug in Scand. J. Dent. Res. 79, 119 ( 1971 ) ) .
Tin ions show a significant anti-caries action and a plaque-inhibiting effect. Firstly, the metabolism of the microorganisms 15 present in the plaque is disrupted (see e.g. J.E. Ellingsen, B.
Svatun and G. Rolla, Acta Odontol. Scand. 38, 219 (1980) and N.
Tinanoff, J.M. Brady and A. Gross, Caries Res. 10, 415 (1976)), and, secondly, tin (II) ions are deposited on the surface of the tooth and form acid-resistant precipitates there, together with 20 fluoride, calcium and phosphate ions (see e.g. J.E. Ellingsen, Scand. J. Dent. Res. 94, 229 (1986) and J.E. Ellingsen and G.
Rolla, Scand. J. Dent . Res . 95, 281 ( 1987 ) ) .
It is therefore the ob~ect of the invention to provide a 25 chlorh~Yi~linl~ adduct which, as an anti-plaque agent, effectively counters the formation and growth of tooth plaque even in very low concentrations, which can desensitize sensitive tooth necks and moreover which, through fluoride release, is capable of protecting the tooth enamel against fi~ n~r;~ atiOn, 30 particularly demineralisation by acids.
This ob~ect is surprisingly achieved by the ~hl~rh~x~in~ adduct according to claim 1 and the process for its production according to claims 2, 3 and 4 and its use according to claims 5 and 6.
` ~ 2~3~92~
- 2a -Preferred embodiments of the invention will now be described, with reference to the accompanying drawings, in which:
Fig 1 is an IR spectrum of the chlorhexidine adduct of the present invention;
Fig 2 is a secondary ions mass spectrometry of Example 3;
Fig 3 is a graph showing f luoride release over time according to Examples 4 and 5; and Fig 4 is a graph showing chlorhexidine release over time c~cording to Exa~l^e 4 .In~l 5.
/
2~9~920 .
The chlnrh~ n~ adduct according to the inventLon is a compound of the following formula:
Cl-~3 -NX-C-~-C~ - ( C~2 ) 6-~H-C-~H-C-~ 3 -C1 ~H NE~ NH ~I
3 ~IF ~IsnFs or its hydrates.
The adduct displays the IR spectrum according to Figure 1. The exact molecular structure of the adduct according to the invention i8 not known. ~3asically, it is possible that the adduct accordlng to the invention consists of electrically neutral molecules or is present in the form of ion5 and hence as a salt.
The adduct according to the invention is produced by reacting a chlr,rh~i~lln~ salt (preferably rhlnrhi~ n.o 1;qll~rnn~te), tin difluoride and hydrogen fluoride in a molar ratio of 1: 1 to 4 4 to 8 in a mixture of 3: l parts by volume ethanol/water as solvent and separating the precipitate formed.
The rhlnrh~ n~ according to the invention is preferably prepared by carrying out the reactLon at room temperature with a chlnrh~Yi~in~ salt to tin ~l~fll~nri~l~ to ILYd~UYI::~ fluoride molar ratio of 1: 4: 6. The yields thus obt~n~hl~ are 90 to almost 100% .
Increased temperatures are dlsadvantageous when carrying out the productlon process since they promote the formation of mi~ed 3 o products with a lower tin f luoride content .
A reaction time of 24 hours is usually sufficient to achieve a complete reaction. The reaction time can, however, vary depending on the reaction parameters selected. The best-suited reaction 2Q9~920 time for the case in question can, however, be ~lPtPrminPfl easily by routine Plrrl~r; ts.
The chlt~rhR~ inP adduct formed by the reaction prP~l~ ;n;-ntly as S precipitate Ls removed and purified, preferably by filtration and subsequent washing with water and acetone. By working-up of the mother liquors, further chlorhexidine adduct can be obtained, so that overall yields of 90 to almost 10096 are obtainable. The purified product is then dried in a conventional way and 10 afterwards exists in the form of hydrates with varying levels of water, dPr~n~lin~ on the degree of drying.
Because of its strong antibacterial action, the chlorhPY;~linP
adduct according to the invention can be used as a therapeutic 15 or prophylactic anti-plaque agent. In doing so, it prevents the formation of plaque and inhibits the growth of films already present on the tooth. Diseases which are caused by the presence of plaque, such as parodontosis, caries and gingivitis, are therefore able to be tackled effectively with the chlorhP~ nP
20 adduct according to the invention. Furthermore, it can contribute to the desensitizing of sensitive tooth necks. It is preferably used in dental materials, such as tooth v~rn;RhP~, fissure sealants, prophylactic pastes, mouthwashes, toothpicks, dental floss, dental chewing-gum, wound dressings, dental creams, 2~ gingiva ~r~;nPrS, disinfectants for protheses and impression materials, drying agents, under-f illing materials, cements, filling materials, adhesives and endodontic materLals . The adduct according to the invention can be deposited on a solid substrate, such as a toothpick or dental floss, or incorporated into dental materials, such as provisional filling materials and fissure sealants .
Of particular advantage is the incorporation of the adduct according to the invention in dental materials which are to remain in the oral cavity for a limited period of time, such as provisional filling materials, wound dressings, impression materials and t-o~rnr~ry cements. If the adduct according to the invention is incorporated for example into a provisional filling material, one obtains, after its removal, a germ-free cavity into 5 which the final filling can immediately afterwards be placed.
Since the chlnrh~ ;; n-~ adduct is only very slightly soluble in common solvents, it is preferably incorporated into the said dental materials as a solid. It is added to the dental materials in quantities of 0.1 to 20 wt.%, preferably 1 to 10 wt.96 and particularly preferably 3 to 7 wt.g~, relative to the total weight of the material. Examples of suitable dental materials are those which contain 10 to 95 wt. 9s poly ~ ~hl e organic binder, 5 to 90 wt.96 inorganic and/or organic fillers and 0.01 to 5 wt.%
15 catalysts, relative to the weight of the total material.
Furthermore, solutions containing 0.03 to 0.001 wt.96 of the adduct according to the invention can be used. Suitable as solvents are e.g. water, ethanol, acetone, ethyl acetate, 20 triethylene glycol dimethacrylate and ~ nef~;nl dimethacrylate.
Further, synthetic or natural resins can be used which are soluble in common solvents and become hard af ter evaporation of the solvent. Examples for such resins are shellac, benzoin resin, 25 polyvinyl pyrrolidone and colophony.
A further preferred application of ~he chlnrh~ i n~ adduct is that as a therapeutic or prophylactic anti-plaque agent. It prevents the formation of plaque and inhibits the growth of plaque already present. Diseases which are caused by the presence 30 of plaque, e.g. parodontosis, primary and secondary caries and gingivitis, can therefore be combatted effectively with the chlorhexidine adduct according to the invention.
As regards its bactericidal effectiveness, the nhlnrh~Yirl;nf~
adduct according to the invention is fully comparable in a _ _ _ _ _ _ _ _ _ _ _ _ . . , . . .... . . . . . . _ . .. . . . ..... _ _ ... . .
2~9~2~
concentration of 0.03 wt.96 with ~hlnrhf~ nP, which at present is regarded as the most effective anti-plaque agent.
Surprisingly, however, the effectiveness of chl~rh~YI~linP is significantly surpassed if both are used in concentrations less 5 than or equal to 0 . 01 wt . 96 . In this concentration range, the chlnrhPY; ~1 i nQ adduct according to the invention is even clearly superior to tin difluoride, a compound known to have very good bactericidal properties.
10 The superiority of the adduct according to the invention especially in low concentrations is of particular significance for practical applications. For, as a result of the rPrr-npnt salivation in the oral cavity, the active ingredients used are continuously diluted. An actlve ingredient, such as the 15 chlorhP~ inP adduct according to the invention, which shows a strong bactericidal effect even in low concentrations, is theref ore of particular advantage .
Finally, the high fluorine content of the adduct ac~nrlin~ to the 20 invention means that it can effect h~r~iPnin~ of the tooth enamel through fluoridization and therefore can also efectively protect against the formation of caries in this respect. The adduct according to the invention further shows the aforementioned effect of tin ions.
The adduct according to the invention can be worked in or applied on dental materials such as inter alia the aorementioned filling compositions, dental v~rni~hP~, fissure sealants, prophylactic pastes, tooth-picks, dental floss, dental chewing-gum, wound 30 dressings, dental creams, gingiva trainers, disinfectants for protheses and impression materials, drying agents, under-filling materials, cements, filling materials, adhesives and endodontic materials, or applied on the teeth in the form of many different dental treatment agents, such as toothpastes, tooth gels, tooth v~rni~hP~ or mouth rinses.
_ _ _ _ .
2~ D
The invention is described in more detail in the following examples .
Example 1 To produce the chlorh~Y;r1;n~ adduct according to the invention, 480 ml ethanol/water (3:1) were introduced first and 12.6 g (0.08 mole) tin difluoride and 6 g of a 40 % HF solution (0.12 mole) dissolved therein. 85 ml (corresponding to 90 g) (0.02 mole) of an aqueous 20% chlorh~Y;~lin~ digluconate solution were added dropwise with stirring within an hour. After a further 5 hours stirring, the precipitate formed was filtered off and washed three times with 50 ml ethanol/water (3:1). Further product crystallised out from the mother liquor within a week. Drying of the precipitate obtained was carried out in the drying cupboard at 50C. The yield of adduct was almost quantitative.
The IR spectrum (RBr pressed disk) is reproduced in Figure 1.
The ~lementary analysis shows that the product is rhl~rh~Y~in~
trihydrofluoride-hydrogen tin trifluoride with 2 moles crystal water.
C22H3ONIocl2 3 HF ~ HSnF3 ~ 2 H20 ~IW = 778 . 2 Elementary analysis:
found theoretical C 34.48% 33.96%
H 4.56% ~.40%
N 18 . 02% 18 . 00%
Cl 9 . 06% 9 . 11%
F 14 . 58% 14 . 65%
Sn 14 . 45% 15 . 259 H2O ) 4 . 84% 4 . 63%
}i20 content de~rmi nl~d by the ~arl Fischer method (Note: The theoretical value of 15 . 2596 for tin is not achieved in the elementary analysig since chlnrh~ nl~
hexahydrof l i~nr~ forms as a by-product during the synthesis in a yield of about 59~. The value for tin therefore falls, whilst a higher value is measured for carbon. ) Solubility:
Water 0 . 03 wt . 96 Ethanol 0 . 02 wt . 96 l~xample 2 The antibacterial effectiveness of the t-hlclrh~r;flinP adduct 15 according to the invention was demonstrated in the agar-diffusion test with StrePtoCOcCuS mutans.
For this, culture suspensions of Stre~tococcus mutans were introduced in liquid yeast-extract-dextrose-agar. After solidification of the agar plates, a basin of 10 mm diameter was cut out. Into this were poured 0.1 ml of the respective test 20 solution. The samples were prepared in duplicate in each case and the diameters of the zones of inhibition were measured after 24-hour incubation at 37C. The results of these tests are set out in the following Table I.
20~9~
g Table I
Inl~bition 2 one diameters Concentration Solution A Solution B SQlution C
0 . 03 wt. % 17 mm 16 mm 20 mm O . 01 wt. 96 13 mm 15 mm ll mm 5 0 . 003 wt . 96 ll mm 11 mm 10 mm no effectiveness Solution A: Aqueous solution of chlorh~Y;~;n~ digluconate Solution B: Aqueous solution of the chlorhf~Y;~;n~ adduct according to the invention Solution C: Aqueous solution of tin dif luoride The test result show that at a concentration of 0 . 03 wt. 96 the antibacterial effectiveness of the chlnrh~Y;~;;n~ adduct according to the invention against Streptococcus mutans i5 comparable with that of ~hlorheY;ci;n~ digluconate, whilst tin difluoride displays an even stronger action at this concentration. With increasing dilution, however, the effectiveness of the known compounds falls sharply, in the case of tin rl;fltlnri~ at a concentration of O . O 0 3 wt . 9~ even to the extent that an anti-bacterial ef f ect can no longer be detected. In contrast to this, the antibacterial effectiveness of the adduct according to the invention is still very high even at concentrations of 0 . Ol to 0 . 003 wt. 96 . Its superiority especially at low concentrations thus makes it a very ef f ective anti-plaque agent .
EYam~le 3 A dental material as described in Example 4 was deposited in a layer of ca. 2 mm on the surface of an absolutely plane-parallel, tin-free hydroxyl-apatite testpiece and polymerised for 40 _ _ . , , . . _ .. _ .. . . _ _ _ _ . .
~992~
seconds with the Heliomat~ (light apparatus from Vivadent).
Afterwards, the thus-coated testpiece was stored for 12 hours at 37C in distilled water. The poly ~ on layer was then removed with microscopic control and the tin content on the 5 hydroxyl apatite surface was analyzed by means of SI~IS (secondary ions mass spectrometry). This analysis process is described in Caries Res. 20, 419 (1986).
~he result obtained is depicted in Figure 2 and shows that a considerable portlon of the tin present in the dental material 10 was deposited on the surface of the hydroxyl apatite.
l~amPle 4 A light-curing fissure sealant contains the following ~ ~ntS:
56 . 08 wt. % Bis-phenol A-glycidyl methacrylate (Bis-Gl~A) 36 .1 wt. % Triethylene glycol dimethacrylate 0 . 45 wt . % Cyanoethylmethyl aniline 0 . 25 wt. % DL-camphor quinone 2.1 wt.% TiO2 0 . 02 wt. % 2, 6-di-tert. -butyl-p-cresol 5 . 0 wt . % Chlorh~ ~ i nf~ adduct The light-curable fissure sealant was obtained by mixing all the components. This was applied with a paint-brush onto the fissures of a molar and cured for 20 sec with the Heliolux' light-curing apparatus from Vivadent/Liechtenstein. The fissures were sealed 25 p-~r---nf-ntly in this way and, through the fluoride release of the chlorhexidine adduct incorporated in the sealant, excellent caries protection was obtained in the occlusal region.
By ;l~lmisring 1 to 5 wt.% of the chl~-rh~Y;-lin~ adduct to the fissure sealant basic formulation, no reduction in the degree of through-hardening was observed, as the following values for .
2Qg9~20 Vickers hardness show:
HV 0 . 5 Fissure sealant without ~h7nrh~ in-~ adduct 188 MPa Fissure sealant + 1% chlnrh~ ;n~ adduct 203 MPa Fissure sealant + 39~ ~hlorh~ in~ adduct 211 NPa Fissure sealant + 5~ chlnrhf~riflin~o adduct 184 ~Pa To demonstrate the chlnrh.oYi-linf~ and fluoride migration, 10 testpieces each with a diameter of 50 mm and a height of 0 . 5 mm were stored in dist. water at 37C. The concentration of fluo:ride ions was det~rmin~d using a fluoro-electrode, and the chlnrh~ 1 i n~ concentration was measured by means of W-10 spectroscopy. The results are set out below in Table II.
Table II
Cumulative fluoride and chlorh~yi~linf~ release ~igration time Fluoride Chlnrh~; ~i i n~
[days] release release [ llm/cm2] [ ,ug/cm2]
1.26 4.30 2 1.97 5.41 3 2.61 5.96 4 3.13 6.36 7 4.57 7.11 5 . 77 8 . 37 17 8 . 01 9 . 07 24 9 . 83 9 . 77 11 . 21 10 . 37 44 13 . 87 10 . 93 86 18 . 49 11 . 01 149 22 . 91 11 . og ` ~Dg~920 The results are represented graphically in Figures 3 and 4.
Examl~le 5 A light-curing dental plastic with relatively high water absorption and theref ore high active ingredient release ( e . g .
5 suitable as provisional filling material or as a wound dressing) has the following composition:
41. 4 wt . % polyester urethane dimethacrylate 0 . 25 wt. % cyanoethylmethyl aniline 0 .15 wt . % DL-camphor quinone 0 . 02 wt . % 2, 6-di-tert . -butyl-p-cresol 33 . 25 wt. % splinter polymerisate l9 . 93 wt. % finely-dispersed silanised SiO2 5 . 0 wt . % chlnrh~ i n~ adduct The splinter polymerisate consists of:
lS 59.4 % urethane dimethacrylate 40 % finely dispersed silanised SiO2 0 . 6 % benzpinacol These c~ ts are mixed together and polymerised at 120C. The filled polymerisate is ground to a polymer powder. The _~huux 20 finely-dispersed silanised SiOz is Aerosil~ OX 50 from Degusaa AG .
A light-curing dental material was obtained by mixing all the ,- ,r.n~ntS.
The water absorption of dental filling composites normally lies 25 in the region of 1 wt. ~ . However, this material shows a water absorption in the region of 3 wt.% (3 weeks EIzO storage at 37C).
Chlnrh~ r1~nf~ and fluoride migration:
. _ _ _ _ 2 ~
The cumulatlve fluoride and chlnrh~xl~lin~ release is 2,, ri~ed in the following table III.
Table III
5 ~ligration time Fluoride Chlorhexidine [ days ] release release [ llm/cm2 ] [ llm/cm2 ]
1.67 10.4 2 2.64 16.3 3 3.52 21.?
4 4 . 29 26 . 5 7 5.64 32.1 6 . 87 37 . 3 17 8.97 43.5 24 10 . 72 49 . 3 11.92 53.5 44 14 . 02 59 . 8 86 17.38 67.3 149 19 . 90 76 . 8 20 The results are represented graphically in Figures 3 and 4.
Microbioloqical action As the migration ~er; Ls show, signif icant quantities of fluoride and chlorh~xi-1~nf~ are released from this dental material, so that even in this combination a suf f icient 25 inhibition of the growth of microorganisms is to be expected.
Since not all microorganisms react equally on released active ingredients, investigations were conducted using the following microbes .
,9.g~
.
Gram-positive bacteria: Streptococcus mutans Staphylococcus aureus Gram-negative bacteria: Pæ~lt~t i~.C auruginOsa Escherichia coli Fun us: Candida albicans 10 g Testpieces (d = 10 mm, h = 2 mm) were introduced into the moist microorganism culture& at 37C over a period of 24 hours and then 15 the zone of inhibition was dett~rmint~
Zone of inhibition diameter [ mm ]
20 Streptococcus mutans 13 Staphylococcus aureus 14 Pseudomonas auruginosa 16 Escherichia coli 14 25 Candida albicans 10 (no effect) With the exception of Candida i~lhit.~n~t, a clear inhibition of growth in these various microorganlsms is detectable.
Claims (6)
1. Chlorhexidine adduct with the following formula 3 HF HSnF3 or its hydrates.
2. A process for preparing the chlorhexidine adduct according to claim 1 comprising:
a) reacting a chlorhexidine salt, tin difluoride and hydrogen fluoride in a molar ratio of 1: 1 to 4 : 4 to 8 in a mixture of 3:1 parts by volume ethanol/water as solvent, and b) separating the resulting precipitate.
a) reacting a chlorhexidine salt, tin difluoride and hydrogen fluoride in a molar ratio of 1: 1 to 4 : 4 to 8 in a mixture of 3:1 parts by volume ethanol/water as solvent, and b) separating the resulting precipitate.
3. A process according to claim 2 comprising:
a) reacting the chlorhexidine salt, tin difluoride and hydrogen fluoride in a molar ratio of 1 : 4 : 6 and b) carrying out step a) at room temperature.
a) reacting the chlorhexidine salt, tin difluoride and hydrogen fluoride in a molar ratio of 1 : 4 : 6 and b) carrying out step a) at room temperature.
4. A process according to claim 2 or 3, wherein chlorhexidine digluconate is used as said chlorhexidine salt.
5. Use of the chlorhexidine adduct or its hydrates according to claim 1 as an antiseptic.
6. Use of the chlorhexidine adduct or its hydrates according to claim 1 as an agent for the prevention of caries.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DEP4222821.2 | 1992-07-08 | ||
DE4222821A DE4222821C2 (en) | 1992-07-08 | 1992-07-08 | Modified chlorhexidine adduct |
Publications (2)
Publication Number | Publication Date |
---|---|
CA2099920A1 CA2099920A1 (en) | 1994-01-09 |
CA2099920C true CA2099920C (en) | 1996-12-24 |
Family
ID=6462979
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002099920A Expired - Fee Related CA2099920C (en) | 1992-07-08 | 1993-07-06 | Modified chlorhexidine-adduct |
Country Status (6)
Country | Link |
---|---|
US (1) | US5393516A (en) |
EP (1) | EP0578344B1 (en) |
AT (1) | ATE141912T1 (en) |
AU (1) | AU655547B2 (en) |
CA (1) | CA2099920C (en) |
DE (2) | DE4222821C2 (en) |
Families Citing this family (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA965340B (en) * | 1995-06-30 | 1997-01-27 | Interdigital Tech Corp | Code division multiple access (cdma) communication system |
US6293287B1 (en) * | 1996-09-13 | 2001-09-25 | Gillette Canada Inc. | UV-cured resin-coated dental floss |
US5967153A (en) * | 1996-10-15 | 1999-10-19 | Gillette Canada Inc. | Emulsion coated dental floss containing chemotherapeutic active agents |
MXPA01003045A (en) * | 1998-09-24 | 2003-07-11 | Advantage Dental Products Inc | Calcified tissue facing preparation containing antimicrobial agent. |
US6726899B2 (en) | 1998-09-24 | 2004-04-27 | Advantage Dental Products, Inc. | Calcified tissue facing preparation containing antimicrobial agent |
DE19921727A1 (en) * | 1999-05-12 | 2000-11-16 | Susanne Szep | Fluoriding composition for treating tooth surfaces to prevent caries and reduce sensitivity, containing hydrogen fluoride to form strongly bound fluoride complexes on surface |
DE19921950A1 (en) * | 1999-05-12 | 2000-11-16 | Susanne Szep | Dentine adhesives containing hydrogen fluoride for use in dental restorative work |
EP1272152B1 (en) * | 2000-04-03 | 2012-03-07 | CHX Technologies Inc. | Use of chlorhexidine in the prevention of root caries |
DE10261241A1 (en) * | 2002-12-20 | 2004-07-15 | 3M Espe Ag | Dental material with bacteriostatic and / or bactericidal substances |
US20060254988A1 (en) * | 2005-05-10 | 2006-11-16 | Confirm Monitoring Systems, Inc. | Methods and compositions for the treatment of water |
EP1787627A1 (en) | 2005-11-17 | 2007-05-23 | 3M Innovative Properties Company | Anti-microbial dental impression material |
AU2006325820B2 (en) | 2005-12-12 | 2013-02-14 | Allaccem, Inc. | Methods and systems for preparing antimicrobial films and coatings |
NZ579785A (en) | 2007-02-21 | 2012-06-29 | Allaccem Inc | Bridged polycyclic compound based compositions for the inhibition and amelioration of disease |
US8188068B2 (en) * | 2007-08-10 | 2012-05-29 | Allaccem, Inc. | Bridged polycyclic compound based compositions for coating oral surfaces in pets |
US8153617B2 (en) * | 2007-08-10 | 2012-04-10 | Allaccem, Inc. | Bridged polycyclic compound based compositions for coating oral surfaces in humans |
US8153618B2 (en) * | 2007-08-10 | 2012-04-10 | Allaccem, Inc. | Bridged polycyclic compound based compositions for topical applications for pets |
US20090074833A1 (en) * | 2007-08-17 | 2009-03-19 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for controlling bone resorption |
US20100016270A1 (en) * | 2008-06-20 | 2010-01-21 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for controlling cholesterol levels |
US20100004218A1 (en) * | 2008-06-20 | 2010-01-07 | Whiteford Jeffery A | Bridged polycyclic compound based compositions for renal therapy |
US20090324516A1 (en) * | 2008-06-27 | 2009-12-31 | Muscle Dave P | Composition and Method for Enhancing Flouride Uptake Using Bioactive Glass |
KR20170058977A (en) | 2014-09-17 | 2017-05-29 | 개리슨 덴탈 솔루션즈, 엘엘씨 | Dental curing light |
RU2696259C2 (en) | 2017-10-23 | 2019-08-01 | Общество С Ограниченной Ответственностью "Сан Системз" | Solubilization of the chlorhexidine base, antiseptic and disinfectant compositions |
DE102019000321A1 (en) | 2019-01-14 | 2020-07-16 | Beuth Hochschule Für Technik Berlin | Oral sustained release polymer composition |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1304090A (en) * | 1970-11-27 | 1973-01-24 | ||
US4069310A (en) * | 1970-11-27 | 1978-01-17 | Colgate Palmolive Company | Method for the manufacture of clear dentifrices |
US5098711A (en) * | 1988-11-14 | 1992-03-24 | Ira Hill | Method of treating the oral cavity with dental floss containing chemotherapeutic agents |
DE4135397C2 (en) * | 1991-10-26 | 1994-01-20 | Ivoclar Ag Schaan | Chlorhexidine adduct, process for its preparation and its use |
-
1992
- 1992-07-08 DE DE4222821A patent/DE4222821C2/en not_active Expired - Fee Related
-
1993
- 1993-06-15 AT AT93250170T patent/ATE141912T1/en not_active IP Right Cessation
- 1993-06-15 EP EP93250170A patent/EP0578344B1/en not_active Expired - Lifetime
- 1993-06-15 DE DE59303552T patent/DE59303552D1/en not_active Expired - Fee Related
- 1993-06-24 AU AU41508/93A patent/AU655547B2/en not_active Ceased
- 1993-07-06 CA CA002099920A patent/CA2099920C/en not_active Expired - Fee Related
- 1993-07-07 US US08/086,919 patent/US5393516A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
AU655547B2 (en) | 1994-12-22 |
DE59303552D1 (en) | 1996-10-02 |
ATE141912T1 (en) | 1996-09-15 |
DE4222821A1 (en) | 1994-01-13 |
EP0578344A1 (en) | 1994-01-12 |
DE4222821C2 (en) | 1994-09-22 |
CA2099920A1 (en) | 1994-01-09 |
EP0578344B1 (en) | 1996-08-28 |
US5393516A (en) | 1995-02-28 |
AU4150893A (en) | 1994-01-13 |
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