Imidazole and imidazolium resins and methods for preparing curable imidazolium antimicrobial resins
Disclosed herein is a composition and method of making a polymerizable antibacterial/antimicrobial resin and using such a bioactive resin in formulated dental compositions.
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This application is a reissue application of U.S. Pat. No. 8,747,831 issued on Jun. 10, 2014, which claims priority to U.S. Provisional Patent Application No. 61/499,910, files filed Jun. 22, 2011.
FIELD OF USEDisclosed herein is a composition and method of making a polymerizable antibacterial/antimicrobial resin and using such a bioactive resin in formulated dental compositions.
BACKGROUNDDental caries are associated with the bacterial contained in dental biofilm. Dental biofilm is complex, with a well-organized structure. Up to 500 bacterial species have been identified in dental biofilm. For oral and systemic health, the dental biofilm needs to be regularly and meticulously removed. Removal and reduction of biofilm can be by mechanical means or mechanical and chemical means. There have been increasing efforts to inhibit the development of biofilm. It is known prior to the development of dental biofilm, the salivary or acquired pellicle forms. This occurs through the adsorption of protein from saliva onto the clean tooth surface. Acquired pellicle formation provides oral bacterial with biding sites, resulting in bacterial adhesion, the first step in the formation of dental biofilm. Therefore, surface modification should inhibit the development of the acquired pellicle and dental biofilm.
In restorative dentistry, secondary caries are well known, which often occurs at the interface between the restoration and the cavity preparation as a result of demineralization of tooth structure due to the dental plaque formation by acid-producing bacteria such as Streptococcus mutans (S. mutans) in presence of fermentable carbohydrates. Thus dental compositions with antibacterial/antimicrobial effect were formulated by incorporation of a variety of antibacterial/antimicrobial agents, such as chlorhexidine, silver ions, and fluoride. Although such low molecular organic compounds demonstrated immediate effectiveness, there are issues related to their long-term effectiveness, potential toxicity and impact to the mechanical strength of the formulated dental composition due to the leachability. On the other hand, solid antibacterial/antimicrobial agents such as silver nanoparticles and polymeric QAS nanoparticles were also developed to address those issues associated with the low molecular weight of antibacterial/antimicrobial agents. There are issues like color stability and optical opacity and mechanical strength. Recently polymerizable antibacterial/antimicrobial resins were developed but their effectiveness varied and most of them demonstrated negative impact on mechanical property of the formulated dental composition.
U.S. Pat. No. 5,494,987 disclosed antimicrobial polymerizable compositions having an ethylenically unsaturated monomer with antimicrobial activity for dental application composed of quaternary ammonium dodecylpyridinium (MDPB).
U.S. Publication No. 2010/0256242 disclosed a polymerizable biomedical composition that includes a quaternary ammonium group bonded at its quaternary sites.
U.S. Pat. Nos. 6,710,181 and 7,094,845 disclosed an imidazole-based silane and monocarboxylic acid salt for improving adhesion between resins and metal or glass.
U.S. Pat. No. 7,553,881 disclosed dental compositions based on polymerizable macromers based on quaternary ammonium salts for antimicrobial effect.
Thus there is strong need to highly effective polymerizable antibacterial resin that is capable to offer a balanced antibacterial effectiveness and excellent mechanical property without severe cytotoxicity. In this invention, a method and composition of polymerizable antibacterial/antimicrobial resins is disclosed and high performance dental compositions are formulated from such novel bioactive resins.
SUMMARYDisclosed herein is a composition and method of making and using such a composition in dental restorations. The composition disclosed herein includes novel polymerizable resins. More specifically, the composition disclosed herein is related to a method of preparing such polymerizable resins that contains multiple imidazole and imidazolium groups and multiple radically polymerizable groups as shown in the following formula:
(A-X)n—Z—(Y—BQR)m
A: polymerizable moiety like methacrylate, acrylate, epoxy, vinylether, etc; n=1, 2, 3, 4 . . . .
B: substituted imidazole moiety like imidazole, methylimidazole, etc, m=1, 2, 3, 4, . . . .
R: a hydrogen atom or an alkyl group having 1-22 carbon atoms
Q: counter ion groups such as halogen atom, chlorine, bromine, iodine, etc
X, Y: equal or different, ether, ester, amide, imide, direct link, alkyl, aromatic, etc,
Z: alkyl, aromatic, etc.
Furthermore, formulated dental compositions, including composite or cements, from this invented polyimidazolium resin are able to offer balanced antibacterial effectiveness and mechanical property without causing any severe cytotoxicity. Such resins may be formulated with conventional resins to provide an improved adhesive to hard tissues in a prepared tooth cavity.
During the attempt to prepare a carbonate-based polymerizable resin (
Accordingly from such a reaction platform, other derivatives may be readily prepared as illustrated in
Further, in order to streamline the process of making such imidazole-based polymerizable resins for use in making imidazolium-based polymerizable resins, a facile process based on imidazole and acrylated resins were investigated as illustrated in
Furthermore, as illustrated in
Such imidazolium-based polymerizable resin was found highly effective in killing bacteria such as S. mutans as showed in
Such effectiveness in killing bacteria for the imidazolium-based polymerizable resins were further demonstrated by the formulated dental composites as showed in Table V and
Obviously from the resin disclosed herein a variety of applications could be found as photopolymerizable dental products. Certainly, it can also be polymerized by heat, and/or redox initiation process. In addition, due to the nature of the imidazole moiety, it is also expected that the disclosed polymerizable resin can also find application in forming a complex with acidic resins or polymers, including PENTA, OEMA, methacrylic acid, polyacrylic acid or reactive acidic glass powders to form a soluble liquid resin, soft gel or hard gel structures or highly-crosslinked solids.
Disclosed herein is a composition and method of making and using such compositions in dental restorations. The composition disclosed herein includes novel polymerizable resins. More specifically, the composition disclosed herein is related to a method of preparing such polymerizable resins that contains multiple imidazole groups and multiple radically polymerizable groups as shown in the following formula:
(A-X)n—Z—(Y—BQR)m
A: polymerizable moiety like methacrylate, acrylate, epoxy, vinylether, etc; n=1, 2, 3, 4 . . . .
B: substituted imidazole moiety like imidazole, methylimidazole, etc, m=1, 2, 3, 4, . . . .
R: a hydrogen atom or an alkyl group having 1-22 carbon atoms
Q: counter ion groups such as halogen atom, chlorine, bromine, iodine, etc
X, Y: equal or different, ether, ester, amide, imide, direct link, alkyl, aromatic, etc,
Z: alkyl, aromatic, etc.
Dental composition disclosed herein may be composed of (1) the functional polymerizable resins contains imidazole group or imidazolium groups described herein in amount of from about 0.5 weight percent to about 99 weight percent of the dental composition, (2) conventional polymerizable resin in amounts of from about 10 weight percent to about 99 weight percent of the dental composition, (3) initiators and other additives in amounts of from about 0.001 weight percent to about 5.0 weight percent of the dental composition, (4) a plurality of filler particles having a size of from about 10 nm to about 100 micron of the dental composition, and (5) an optional inert solvent in amounts not to exceed 1 weight percent of the dental composition.
HEMA and HPMA are typical monomethacrylate resins; BisGMA, TEGDMA, UDMA are typical conventional dimethacrylate resins, which are polymerizable/curable by heat, light and redox initiation processes. CQ and LTPO are typical photoinitaiors. Tertiary aromatic amines, such as EDAB, may be included as an accelerator for CQ-based photoinitiator. Other additives such as inhibitors, UV stabilizers or fluorescent agents may also be used. In addition, a variety of particles, polymeric, inorganic, organic particles may be incorporated to reinforce the mechanical properties, rheological properties and sometime biological functionalities.
The following abbreviations may be used:
- BisGMA: 2,2-bis(4-(3-methacryloyloxy-2-hydroxypropoxy)-phenyl)propane
- HEMA: 2-hydroxyethyl methacrylate
- HPMA: 2-hydroxypropyl methacrylate
- TEGDMA: triethylene glycol dimethacrylate
- UDMA: di(methacryloxyethyl)trimethyl-1,6-hexaethylene-diurethane
- BHT: butylhydroxytoluene
- CQ; camphorquinone
- LTPO: lucirin TPO/2,4,6-trimethylbenzoyldiphenylphosphine oxide
- EDAB: 4-Ethyl dimethylaminobenzonate
- AMAHP: 3-(acryloyloxy)-2-hydroxypropyl methacrylate
- EGAMA: ethyleneglycol acrylate methacrylate
- TCDC: 4,8-bis(hydroxymethyl)-tricyclo[5,2,1,02.6]
- CDI: 1,1-carbonyl-diimidazole
- SR295: pentaerythritol tetraacrylate
Isosorbide-based Bisimidazole-dimethacrylate Resin (XJ8-9/
TCDC-based Bisimidazole-dimethacrylate Resin (XJ8-13/
HEMA-based Monoimidazole-dimethacrylate Resin (XJ8-6/
HEMA-based Monoimidazole-dimethacrylate Resin (XJ8-48/
AMAHP-based monosimidazole-methacrylate Resin (XJ8-111/
EGAMA-based monosimidazole-methacrylate Resin (XJ8-157/
HEMA-based Monoimidazoliumbromide-dimethacrylate Resin (XJ8-45/
Isosorbide-based Bisimidazoliumbromide-dimethacrylate Resin (XJ8-31/
HEMA-based Monoimidazoliumbromide-dimethacrylate Resin (XJ8-40/
HEMA-based Monoimidazoliumbromide-dimethacrylate Resin (XJ8-54/
HEMA-based Monoimidazoliumbromide-dimethacrylate Resin (XJ8-80/
Bis(3-dodecanylimidazoliumbromide)-Bisacrylate Resin (XJ8-152-1/
EGAMA-based monoimidazoliumbromide-monomethacrylate Resins (XJ8-160/
AMAHP-based monosimidazolium-methacrylate Resin (XJ8-88/
AMAHP-based monosimidazolium-methacrylate Resin (X18-94/
AMAHP-based monosimidazolium-methacrylate Resin (XJ8-88/
Light curable flowable dental composites (IJ1-84-2 and IJ1-85-2) containing polymerizable imidazlium resin (XJ8-80 at 2-4% wt/wt) were formulated with 60% of filler, which demonstrated effective antibacterial activities as showed in Table VI.
Example 16-17Light curable universal dental composites (XJ8-136 and XJ8-137) containing polymerizable imidazlium resin (XJ8-80 at 20.9-1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities and excellent mechanical properties without causing severe cytotoxicityas as showed in Table VI.
Example 18-21Light curable universal dental composites (IJ1-115, 117, 118, and 137) containing polymerizable imidazlium resin (XJ8-80 at 0.9-1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities and excellent mechanical properties without causing severe cytotoxicityas showed in Table VIII.
Example 22-25Light curable universal dental composites (IJ2-39, 40, 41, and 42) containing polymerizable imidazlium resin (XJ8-152 at 0.9-1.8% wt/wt) were formulated with 82% of filler, which demonstrated excellent mechanical properties as showed in Table X.
Example 26-29Light curable universal dental composites (IJ2-189, 190, 191, and 192) containing polymerizable imidazlium resin (XJ8-160 at 0.9-1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities and excellent mechanical properties as showed in Table XII.
Example 30Light curable universal dental composites (IJ2-205) containing polymerizable imidazlium resin(XJ8-88 at 1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities as showed in Table XIV.
Example 31Light curable universal dental composites (IJ2-206) containing polymerizable imidazlium resin(XJ8-94 at 1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities as showed in Table XIV.
Example 32Light curable universal dental composites (IJ2-207) containing polymerizable imidazlium resin(XJ8-54 at 1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities as showed in Table XIV.
Example 33Light curable universal dental composites (IJ2-208) containing polymerizable imidazlium resin(XJ8-114 at 1.8% wt/wt) were formulated with 82% of filler, which demonstrated effective antibacterial activities as showed in Table XIV.
Comparative Example 1-2Light curable universal dental composites (IJ1-138 and 139) were formulated with 82% of filler, which demonstrated excellent mechanical properties as showed in Table VIII.
Comparative Example 3Light curable universal dental composites (IJ1-171) were formulated with 82% of filler, which demonstrated excellent mechanical properties as showed in Table XIV.
It will be appreciated that various of the above-disclosed and other features and functions, or alternatives thereof, may be desirably combined into many other different systems or applications. Also, various presently unforeseen or unanticipated alternatives, modifications, variations or improvements therein may be subsequently made by those skilled in the art, and are also intended to be encompassed by the following claims.
Claims
1. A dental curable antimicrobial composition comprising:
- from about 0.1 weight percent to about 5.0 weight percent of an imidazolium-based polymerizable resin;
- from about 5 weight percent to about 60 weight percent of a non-imidazolium-based polymerizable resin;
- from about 0.005 weight percent to about 5 weight percent of at least one of a photoinitiator, a thermal/redox initiator or other additive;
- from about 40 weight percent to about 90 weight percent of a glass filler having a particle size of from about 10 nm to about 100 microns; and
- an optional inert solvent
- wherein the imidazolium-based polymerizable resin has a formula of: (A-X)n—Z—(Y—B—HRQR)m
- wherein A is a polymerizable moiety selected from the group consisting of methacrylate, acrylate, epoxy and vinylether,
- wherein B is an imidazole or a methyl imidazole imidazolium moiety,
- wherein R is a hydrogen atom or an alky group having from 1 to 22 carbon atoms,
- wherein H Q is a halogen atom, a chlorine atom, a bromine atom or an iodine atom an imidazolium counter ion,
- wherein X and Y are the same or different and are an ether, ester, amide, imide, direct link, alkyl, or aromatic,
- wherein Z is an alkyl or an aromatic, and
- wherein n and m are integers of at least 1.
2. The dental curable antimicrobial composition according to claim 1, wherein the imidazolium-based polymerizable resin demonstrates antibacterial activity capable of killing at least 99 percent of S. mutans.
3. The dental curable antimicrobial composition according to claim 1, wherein the dental composition in its entirety is capable of an imidazolium-based polymerizable resin demonstrates antibacterial activity capable to of killing more than 99 percent of S. mutans and S. aureus.
4. A curable antimicrobial composition according to claim 1, wherein the imidazolium-based polymerizable resin is an alkylimidazoliumbromide-dimethacrylate resin having a formula selected from:
5. A curable antimicrobial composition comprising: at least one ionic imidazolium moiety, and a polymerizable moiety, the imidazolium-based polymerizable resin selected from a HEMA-based monoimidazoliumbromide-dimethacrylate resin, a 3-dodecanylimidazoliumbromide-dimethacrylate resin, a bis(3-dodecanylimidazoliumbromide)-bisacrylate resin, a bis(3-butylimidazoliumbromide)-bisacrylate resin, a EGAMA-based monoimidazoliumbromide-monomethacrylate resin, a 3-dodecanylimidazoliumbromide-monomethacrylate resin, a AMAHP-based monoimidazolium-methacrylate resin, a isosorbide-based bisimidazoliumbromide-dimethacrylate resin, a isosorbide-based bis(3-butylimidazoliumbromide)-dimethacrylate resin, and a 1,6-hexane-bisimidazoliumbromide-dimethacrylate resin.
6. A curable antimicrobial composition according to claim 5, wherein the imidazolium-based polymerizable resin having a formula selected from:
- (a) a bisimidazolium-dimethacrylate resin that has a formula selected from one of a: an isosorbide-based bisimidazoliumbromide-dimethacrylate resin
- a bis(3-dodecanylimidazoliumbromide)-bisacrylate resin
- a bis(3-butylimidazoliumbromide)-bisacrylate resin
- A 1,6-hexane-bisimidazoliumbromide-dimethacrylate resin
- (b) a monoimidazolium-dimethacrylate resin that has a formula of a HEMA-based monoimidazoliumbromide-dimethacrylate resin
- (c) a monoimidazolium-dimethacrylate resin that has a formula of a EGAMA-based monoimidazoliumbromide-monomethacrylate resin
7. A curable antimicrobial composition according to claim 5, wherein the imidazolium-based polymerizable resin is present from about 0.1 weight percent to about 20.0 weight percent, based on the total weight of the composition.
8. A curable antimicrobial composition according to claim 7, comprising: one or more acidic resins or polymers, or reactive acidic glass powders complexed with the imidazolium-based polymerizable resin to form one of a soluble liquid resin, soft gel, hard gel and highly-crosslinked solid.
9. A curable antimicrobial composition according to claim 8, comprising:
- about 5 weight percent to about 99 weight percent of a non-imidazolium based polymerizable resin;
- from about 0.001 weight percent to about 5 weight percent initiators and other additives;
- from about 40 weight percent to about 90 weight percent of filler particles having a size of from about 10 nm to about 100 micron,
- an optional inert solvent,
- wherein all weight percents are based on the total weight of the curable antimicrobial composition.
10. A curable antimicrobial composition according to claim 8, comprising: wherein the imidazolium-based polymerizable resin is present from about 0.1 weight percent to about 5.0 weight percent, and wherein all weight percents are based on the total weight of the curable antimicrobial composition.
- from about 5 weight percent to about 60 weight percent of a non-imidazolium-based polymerizable resin;
- from about 0.005 weight percent to about 5 weight percent of at least one of a photoinitiator, a thermal/redox initiator or other additive;
11. A curable antimicrobial composition according to claim 10, comprising wherein the imidazolium-based polymerizable resin is present from about 0.9 weight percent to about 1.8 weight percent, and wherein all weight percents are based on the total weight of the curable antimicrobial composition.
- about 80 weight percent of a glass filler having a particle size of from about 10 nm to about 100 microns; and
12. A curable antimicrobial composition comprising:
- an imidazolium-based polymerizable resin comprising: at least one polymerizable group, and at least one imidazolium moiety comprising a linear long alkyl chain of from eight to fourteen carbon atoms.
13. A curable antimicrobial composition according to claim 12, the at least one polymerizable group selected from methacrylate, acrylate, epoxy and vinylether.
14. A curable antimicrobial composition according to claim 12, the at least one polymerizable group selected from acrylate, methacrylate and polyacrylate.
15. A curable antimicrobial composition according to claim 14, the at least one polymerizable group comprising two methacrylate groups, and the at least one imidazolium moiety comprising a linear alkyl chain of twelve carbon atoms.
16. A curable antimicrobial composition according to claim 12 having a formula selected from:
- a HEMA-based monoimidazoliumbromide-dimethacrylate resin
- a EGAMA-based monoimidazoliumbromide-monomethacrylate resin
17. A curable antimicrobial composition according to claim 12, wherein the imidazolium-based polymerizable resin is present from about 0.1 weight percent to about 20.0 weight percent based on the total weight of the composition.
18. A curable antimicrobial composition according to claim 17, comprising: one or more acidic resins or polymers, or reactive acidic glass powders complexed with the imidazolium-based polymerizable resin to form one of a soluble liquid resin, a gel, and a crosslinked solid.
19. A curable antimicrobial composition according to claim 18, comprising:
- about 5 weight percent to about 99 weight percent of a non-imidazolium based polymerizable resin;
- from about 0.001 weight percent to about 5 weight percent initiators and other additives;
- from about 40 weight percent to about 90 weight percent of filler particles having a size of from about 10 nm to about 100 micron,
- an optional inert solvent,
- wherein all weight percents are based on the total weight of the curable antimicrobial composition.
20. A curable antimicrobial composition according to claim 18, comprising: wherein the imidazolium-based polymerizable resin is present from about 0.1 weight percent to about 5.0 weight percent, and wherein all weight percents are based on the total weight of the curable antimicrobial composition.
- from about 5 weight percent to about 60 weight percent of a non-imidazolium-based polymerizable resin;
- from about 0.005 weight percent to about 5 weight percent of at least one of a photoinitiator, a thermal/redox initiator or other additive;
21. A curable antimicrobial composition according to claim 20, comprising wherein the imidazolium-based polymerizable resin is present from about 0.9 weight percent to about 1.8 weight percent, and wherein all weight percents are based on the total weight of the curable antimicrobial composition.
- about 80 weight percent of a glass filler having a particle size of from about 10 nm to about 100 microns; and
22. A curable antimicrobial composition according to claim 12,
- wherein the imidazolium-based polymerizable resin has a formula of: (A-X)n—Z—(Y—B—QR)m
- wherein A is a polymerizable moiety selected from the group consisting of methacrylate, acrylate, epoxy and vinylether,
- wherein B is an imidazole or a methyl imidazole,
- wherein R is a hydrogen atom or an alky group having from 1 to 22 carbon atoms,
- wherein Q is an imidazolium counter ion,
- wherein X and Y are the same or different and are an ether, ester, amide, imide, direct link, alkyl, or aromatic,
- wherein Z is an alkyl or an aromatic, and
- wherein n and m are integers of at least 1.
23. A curable antimicrobial composition according to claim 22, wherein Q is a halogen.
24. A curable antimicrobial composition according to claim 22, wherein Q is selected from chlorine, bromine, and iodine.
25. An imidazole-based precursor for forming an imidazolium-based polymerizable resin, comprising: a polymerizable imidazole-based resin selected from a monoimidazole resin and a polyimidazole(meth)acrylate resin, the moniomidiazole resin having a formula selected from: the polyimidazole(meth)acrylate resin having a formula selected from:
26. An imidazole-based polymerizable resin comprising: an imidazole moiety, the imidazole-based polymerizable resin selected from a isosorbide-based bisimidazole-dimethacrylate resin, a TCDC-based bisimidazole-dimethacrylate resin, a butanediol-based bisimidazole-dimethacrylate resin, a TCDC-based bisimidazole-dimethacrylate resin, a paraxylenediol-based bisimidazole-dimethacrylate resin, a HEMA-based monoimidazole-dimethacrylate Resin, a AMAHP-based monoimidazole-monomethacrylate resin, and a EGAMA-based monoimidazole-monomethacrylate.
27. A curable antimicrobial composition according to claim 26, wherein the imidazole based polymerizable resin has a formula selected from:
- (a) a bisimidazole-dimethacrylate resin that has a formula selected from: a isosorbide-based bisimidazole-dimethacrylate resin
- a TCDC-based bisimidazole-dimethacrylate resin
- CDI-based reaction pathways to bisimidazole-dimethacrylate resins
- a butanediol-based bisimidazole-dimethacrylate resin
- a paraxylenediol-based bisimidazole-dimethacrylate resin
- (b) a Monoimidazole-dimethacrylate resin that has a formula: a HEMA-based monoimidazole-dimethacrylate resin
- (c) a monoimidazole-methacrylate resin that has a formula selected from: a AMAHP-based monoimidazole-methacrylate resin
- a EGAMA-based monoimidazole-methacrylate resin
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Type: Grant
Filed: Jun 3, 2016
Date of Patent: Jul 16, 2019
Assignee: DENTSPLY SIRONA INC. (York, PA)
Inventor: Xiaoming Jin (Middletown, DE)
Primary Examiner: Timothy J. Kugel
Application Number: 15/172,640
International Classification: A61K 31/74 (20060101); A61K 6/00 (20060101); A61K 6/083 (20060101);