EP1126792A1

EP1126792A1 - Antimicrobial compositions that protect skin and dental tissue

Info

Publication number: EP1126792A1
Application number: EP99961586A
Authority: EP
Inventors: Salim A. Nathoo; R. Eric Montgomery
Original assignee: Individual
Current assignee: Individual
Priority date: 1998-11-04
Filing date: 1999-11-04
Publication date: 2001-08-29
Also published as: AU1813300A; WO2000025697A1

Abstract

Disclosed are compositions containing at least one anti-microbial agent and at least one volatile solvent. The compositions are applied to biological substrates such as skin, keratinous tissue (e.g., finger nails and toenails) and dental tissue (e.g., teeth and surrounding soft tissue). A residue of the anti-microbial agent is left on the substrate, inhibiting microbial growth for a given period of time. The compositions are particularly useful in the course of dental procedures. In these embodiments, they are applied to teeth that have been drilled or otherwise prepared to receive a dental restorative composition such as a filling or crown, or a dental prosthetic device.

Description

ANTIMICROBIAL COMPOSITIONS THAT PROTECT SKIN AND DENTAL

TISSUE This application claims priority under 35 U.S.C. 119(e)(1) from United States Provisional Application No. 60/107,026, entitled "Antimicrobial Film- Forming Compositions", filed November 4, 1998, the contents of which are hereby incorporated by reference in their entirety. TECHNICAL FIELD

The invention relates in general to anti-microbial film-forming compositions for placement in contact with biological surfaces, together with methods for their use. The invention relates more particularly to anti-microbial film- forming compositions that are placed at the interface between a biological surface and the surface of a prosthetic material in order to prevent the growth of microorganisms. BACKGROUND ART A wide variety of disinfectants, sanitizers, and sterilants is available for use in a clinical or surgical environment to destroy bacteria and prevent infections. Such compositions may be applied to the surface of the skin for the purpose of destroying microorganisms before they can be transferred to another surface during critical procedures. Alternatively, a hard, inanimate surface may be contacted with an anti-microbial composition in order to eliminate or reduce the number of microorganism residing thereon. It is desirable for such compositions to provide a sufficient amount of one or more active anti-microbial agents on the surface (whether biological or inanimate) in order to prolong the microorganism-free or microorganism-reduced state. Compositions used in the dental office for preparation of a tooth surface prior to placement of a resin-based restorative material generally do not contain agents that can control microbial growth. Cavity cleansers are an exception because they often contain water-soluble anti-microbial agents and detergents that are used to cleanse and disinfect the space created after removing carious enamel and/or dentin. However, cavity cleansers are rinsed from the tooth surface following a short contact time, thereby limiting the ability of these compositions to protect the tooth surface from future microbial contamination. Tooth conditioning agents are aqueous solutions of decalcifying agents (e.g. phosphoric acid). They are used to create surface irregularities prior to application of the restorative material (thus increasing mechanical retention). They are placed in contact with the tooth surface for a period of about 15 to 60 seconds, again, before being rinsed off with water. Tooth surface primers, such as those used to create a bond between the natural dentin or enamel surface and a restorative material, typically contain compounds (such as unsaturated carboxylic acids) designed to bridge the interface between the biological and the restorative surfaces. Such compounds generally show little, if any, anti-microbial activity.

Compositions such as Alpha-Dent™ Cavity Cleanser (Alphadental Products Co.; Chicago, IL) are used to cleanse the tooth structure prior to the placement of a restorative material. This composition contains about 2% by weight of chlorhexidine (the salts of which are water-soluble, cationic anti-microbial agents) in order to destroy any residual bacteria within a tooth preparation prior to the placement of a restorative material. Although chlorhexidine salts are acceptable for killing microorganisms in the oral cavity (these compounds have been thoroughly investigated for safety and efficacy), they are not well suited for placement at the interface between a biological surface and a resin-based restorative. Cationic compounds such as chlorhexidine, when allowed to reside on oral surfaces for an extended time, are known to facilitate the formation of tooth stains. In addition, cationic anti-microbial compounds tend to form salts with the adhesion-promoting carboxylate or phosphate moieties found in modem dentin and enamel bonding agents. Such salt formation leads to precipitation of insoluble adducts at the interface which at best, causes attenuation of the strength of adhesion promoters in many cases, simply renders them useless.

Another preparative composition purported to have anti-microbial activity is described in U.S. Patent No. 5,385,728. It is commercially available (Bisco Dental Products; Schaumburg, IL) as a dentin and enamel etchant. Such compositions are utilized to etch the dentin and/or enamel (through dissolution of hydroxyapatite crystals) for the purpose of creating surface porosity. The porous tooth surface is more readily penetrated by adhesion promoters, thus creating a mechanical bond upon polymerization of the bonding agent and restorative material. The patent describes methods for treating tooth enamel or dentin involving etching or partial decalcification of said enamel or dentin, the improvement comprising the use of benzalkonium chloride as an anti-microbial agent, together with a suitable etching compound (preferably an aqueous solution of phosphoric acid) in a single-step application. In addition to the tooth staining problems associated with cationic anti-microbial compounds, the use of water-soluble cationic anti-microbial agents in a tooth etching composition at concentrations that would not interfere with the adhesion process would unlikely be able to prevent future microbial growth.

Another class of compositions contains hydrogen peroxide or sodium hypochlorite. These compounds oxidatively destroy bacteria and debride root canals during root canal or endodontic therapy but at the same time are highly susceptible to reduction in activity in the presence of bodily fluids such as blood and saliva. A major drawback of the use of anti-microbial oxidizing agents is the reduction in bond strength observed with resin-based restorative materials placed in contact with a biological surface that has been oxidized. It is postulated that the increase in oxygen at the interface between the restorative material (or its attendant bonding agent) and the tooth preparation surface inhibits the polymerization reaction. The lower degree of polymerization at the interface thus causes a reduction in overall bond strength between the tooth surface and the restorative material.

Despite attempts to provide compositions and methods for preventing interfacial infections between the tooth surface and a restorative material, the incidence of recurrent caries still remains quite high. Other contributing factors may be poor marginal adaptation of the restoration due to shrinkage of the restorative material during polymerization and poor adhesion to the tooth surface. Infiltration at the restoration margins by oral fluids (together with oral microorganisms) under such circumstances can easily lead to secondary caries. Thus, in the absence of perfect marginal adaptation and/or a perfect bond between the tooth surface and the restorative material, there is a need for compositions that of exert an anti-microbial effect at the interface between the tooth surface and a resin-based restorative material for extended periods of time. Some film-forming compositions, such as cosmetics, are placed on the body surface in order to enhance personal attractiveness, to moisturize the skin, and (more recently) to prevent the growth of microorganisms. Preservative agents, such as methyl- and propylparabens, isochlorothiazolinones, phenolics and hydantoin compounds, are added to provide resistance to microbial growth in the package. An additional benefit is that anti-microbial compounds used to preserve a cosmetic preparation also provide a certain degree of germ killing on the surface of the skin when present as a part of the residual film (usually oil-based left behind after all or most of the volatile components of the composition such as water and fragrance have evaporated). Care must be taken not to include a level of preservative sufficient to cause irritation, inflammation, or sensitization of the skin.

Cleaning compositions such as anti-microbial hand washes and deodorant soaps are also widely available. These compositions are not suitable for cleansing tooth surfaces prior to placing a restorative material due to the presence of high levels of both surfactants and water. Surfactants are irritating after extended contact and must be rinsed from the body surface. Cleansing surfactants also create a boundary layer at an interface between two materials, thus rendering them highly undesirable for use on a tooth surface preparation. High levels of water are also undesirable, due to the reduction in bond strength between the tooth surface and the resin-based restorative observed in the presence of excess moisture. Thus, there is a need for antimicrobial compositions that can be placed directly onto a dental surface such as a tooth (and which may include the surrounding soft tissue) prepared for receiving a restorative material such as a filling or a dental prosthetic device such as a crown or brace, for the specific purpose of preventing microbial growth at the interface between the two surfaces (tooth and restorative or device). Stated in more general terms, there is a need for compositions and methods that protect against infection by pathogenic organisms at the interface between a biological substrate and a prosthetic material adhered thereto. SUMMARY OF THE INVENTION

One aspect of the present invention is directed to an anti-microbial composition that is applied to or contacted with a biological substrate. The application of the composition results in a residue of an anti-microbial agent being left on the surface which provides anti-microbial activity for an extended period of time. The compositions contain an anti-microbial agent and at least one volatile solvent. Film-forming agents (also known as anti-microbial retention enhancing agents), and other agents that increase the penetration of the residue e.g., phosphoric acid, alpha hydroxy acids and chelating agents may also be present. In preferred embodiments, the anti-microbial agent is non-cationic and water-insoluble. The compositions are free of polishing agents, surfactants and in more preferred embodiments, water, to maximize the retention of the anti-microbial agent on the surface while reducing the time necessary for the residue to form. Preferred volatile solvents are organic solvents having fewer than 12 carbon atoms e.g., ethanol, isopropanol, acetone, ethyl acetate, diethyl ether, propionaldehyde and dichloromethane. More preferred solvents are ethanol and acetone. The compositions are simply applied to the biological substrate such as skin, keratinous tissue or dental tissue and allowed to dry. The residue of the anti-microbial agent left on the substrate inhibits microbial growth for a given period of time.

In other preferred embodiments, the compositions are used in the course of various dental procedures, as dental primers. They are applied to or contacted with dental tissue (e.g., teeth and surrounding soft tissue) that has been treated by a clinician for purposes of applying a dental restorative compostion or a prosthetic device. What remains on the dental tissue is a residue or preferably, a film or layer of the anti-microbial agent. Optionally, a film-forming polymer is included in the primer to enhance the even distribution of the anti-microbial agent over the dental surface. In yet other embodiments, the anti-microbial agent also possesses analgesic and/or anti-inflammatory properties. Other agents possessing these properties may also be present. In yet other preferred embodiments, an organosilane is the sole solvent or one of the solvents included in the composition.

Another aspect of the invention is directed to a dental adhesive composition containing a dental adhesive and a water-insoluble anti-microbial agent. The adhesive is preferably a bonding agent. In preferred embodiments, the composition also contains a polymerizable solvent and a polymerization initiator. The present invention also provides methods of applying the adhesive composition to or contacting it with a dental surface prior to the application of the restorative composition or the prosthetic device. Another aspect of the present invention is directed to a method for bonding a dental restorative composition or prosthetic device to a dental surface. The method involves applying to or contacting the tooth with the dental primer, allowing a residue of the anti-microbial to form, applying to or contacting the tooth with the dental adhesive composition, allowing the dental adhesive and the anti-microbial agent to dry and then applying the restorative composition or device. Both the primer composition and the adhesive composition contain an anti-microbial agent, which may be the same or different, preferably the same.

Biological surfaces treated with preferred embodiments of the invention have been shown to resist microbial growth and colonization after being contacted with microorganisms. In addition, applicants have demonstrated that microbial growth was inhibited in microbiologically contaminated biological surfaces treated with preferred embodiments of the present invention. BEST MODE OF CARRYING OUT INVENTION

In preferred embodiments, the anti-microbial compositions of the present invention are used to pre-treat or prime dental surfaces which are to be joined with restorative or reconstructive compositions such as fillings or dental or orthodontal prostheses or devices such as crowns, caps, dentures and braces. The compositions are not dentifices, mouthwashes or flosses. Thus, the compositions are said to "consist essentially of the solvent and the anti-microbial and thus exclude polishing agents, surfactants and more generally, any substance that would detract from the final result, namely leaving a residue or film of the anti-microbial agent on the dental surface or skin. The compositions, however, may further contain film forming agents and penetration enhancing agents such as phosphoric acid, hydrochloric acid, acetic acid and alpha hydroxyacids such as citric and tartaric acids. Chelating agents such as phosphonic acids and EDTA may be included as well. The compositions may be applied to the buccal cavity and the dental tissues by rinsing or directly (such as by way of applicator or finger). In other embodiments, the antimicrobial compositions are applied to external (i.e., non-oral) skin.

In general, any anti-microbial agent that is non-toxic, forms a residue on skin or dental tissue and provides anti-microbial activity thereon. Examples include bisbiguanides such as chlorhexidine and phenolic compounds such as thymol, methyl salcylate, eucalyptol and menthol. In the broadest sense, the level of antimicrobial compound included in the composition is the minimum concentration that prevents the growth of microorganisms on the surface of and within a limited zone around the dental composition or device for an extended period of time. An extended period of time is herein defined as the amount of time during which the cured composition is in contact with the biological surface and during which the cured composition is exposed to potential colonization by one or more microorganisms. Preferred extended times include from a few days, to a few weeks to few months and even years. In general, the anti-microbial agent is present in the composition in an amount of from about 0.05% to about 30%. Smaller amounts e.g., between about 0.05% and about 10% by total weight of the composition, are preferred.

Preferred antimicrobials are water-insoluble (e.g., having a solubility in distilled water at 25 C of less than 1,000 ppm) and non-cationic. Classes of antimicrobials that are water-insoluble and non-cationic include halogenated diphenyl ethers (e.g., 2',4,4'-trichloro-2-hydroxy-diphenyl ether and 2,2'-dihydroxy-5,5'- dibromo-diphenyl ether); halogenated salicylanilides (e.g., 4', 5- dibromosalicylanilide, 3,4',5-trichlorosalicylanilide, 3,4',5-tribromosalicylanilide, 2,3,3',5-tetrachlorosalicylanilide, 3,3,3', 5-tetrachlorosalicylanilide, 3,5-dibromo-3'- trifluoromethyl salicylanilide, 5-n-octanoyl-3'-trifluoromethyl salicylanilide, 3,5- dibromo-4'-trifluoromethyl salicylanilide and 3,5-dibromo-3'-trifluoro methyl salicylanilide (fluorophene)); benzoic esters (e.g., methyl-, ethyl-, propyl- and butyl- p-hydroxybenzoic ester); halogenated carbanalides (e.g., 3,4,4'Jrichlorocarbanilide, 3-trifluoromethyl-4,4'-dichlorocarbanilide and 3,3,4'-trichlorocarbanilide); and phenolic compounds (e.g., phenol and its homologs, mono- and poly-alkyl and aromatic halo (F, Cl, Br and I)-phenols, resorcinol and catechol and their derivatives and bisphenolic compounds). Representative compounds are set forth in U.S. Patent 5,344,641. The more preferred antimicrobial agents are substantially water-insoluble members of the halogenated diphenyl ether group and the phenolic group, in particular those compounds described in detail in U.S. Patents 4,894,220 and 5,800,803. See also U.S. Patents 5,665,333 and 5,686,064.

The most preferred water-insoluble antimicrobial agent (herein defined as an antimicrobial compound having a solubility in distilled water at 25 °C of less than 1000 ppm) is triclosan (trade name Irgasan DP300). Triclosan (2,4,4'- trichloro-2'-hydroxydiphenyl ether, CAS No. 338034-5) is a broad spectrum antimicrobial with a molecular weight of 289.5, having very limited water solubility at physiological temperatures (20 ppm in distilled water at 20°C and 40 ppm in distilled water at 50°C). The safety of triclosan has been well established and its use in oral care products, primarily water-based toothpastes in which the triclosan, typically at a concentration of about 0.30 percent by weight, has been solubilized. The preferred amount of triclosan is from about 0.05% to about 30%; the more preferred amount is from about 0.05% to about 10%; and the most preferred range is from about 0.05% to about 1% by total weight of the composition. The solvents useful in the compositions of the present invention may be aqueous or substantially non-aqueous in nature. The solvent or solublizer provides a vehicle to deliver the anti-microbial agent to the dental tissue. The amount of solvent in the composition ranges from about 30% to about 99.99% by total weight of the composition, and preferably from about 95% to 99.99%. It is volatile in the common and everyday sense in that it evaporates readily at normal pressures and temperatures. Alternatively, it can be caused to partially or totally evaporate within a suitable period of time to allow the overall dental procedure to move along in relatively uninterrupted fashion. Thus, it is preferred that the composition is substantially non-aqueous (e.g., excluding water with the exception of water contained in commercial preparations of volatile organic solvents such as isopropanol). Preferred solvents are substantially non-aqueous in nature and include alcohols, keytones, aldehydes, esters, and ethers having fewer than 12 carbon atoms, and mixtures thereof. Examples include ethanol, acetone, propionaldehyde, ethyl acetate and diethyl ether. Other preferred non-aqueous solvents include organosilanes such as methacryloxypropyltrimethoxysilane.

The compositions of the present invention may also contain a film- forming polymeric material. The purpose of this ingredient is to enhance the retention of the anti-bacterial residue on the dental tissue for an extended period of time. This type of ingredient is well known in the art, and is disclosed, for example, in U.S. Patent 5,344,641 in terms of an antibacterial-enhancing agent. Preferred film- forming polymers include acrylates, mefhacrylates, celluloses, polycarboxylates, polyvinyl methyl ether/maleic copolymers, and combinations thereof.

In a preferred embodiment of this aspect of the present invention, the composition is in the form of a dental primer. The purpose of the primer, as described in more detail below, is to pre-treat a tooth that has been drilled or prepared to adapt it to receive a dental restorative composition or a dental prosthetic device. When used as a dental primer, it is preferred that the anti-microbial agent also possesses analgesic and/or anti-inflammatory activity. Triclosan, for examples possesses analgesic and anti-inflammatory properties. Otherwise, an analgesic and/or anti-inflammatory agent may be provided separately. The preferred solvent is an organosilane.

Another aspect of the invention is directed to a dental adhesive composition. The adhesive contains a water-insoluble anti-microbial agent and a bonding agent. The solvent is not necessary. Bonding agents may be light-curable or chemically cured. Examples includes urethane dimethacrylate, methacryloyloxyethyl maleate, triethyleneglycol dimethacrylate and bisphenol A-glycidyl methacrylate. In more preferred embodiments, the adhesive compositions contain a polymerizable solvent. The solvent is contained in the composition in an amount of from about 2% to about 90%, preferably from about 2% to about 30%, and more preferably from about 2% to about 15% by weight of the composition. Mefhacrylates are the preferred polymerizable non-aqueous solvents. Representative mefhacrylates include methyl methacrylate, ethyl methacrylate, n-propyl methacrylate, isopropyl methacrylate, n-butyl methacrylate, isobutyl methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, hydroxybutyl methacrylate, propylene glycol monomethacrylate, polyethylene glycol) monomethacrylate, isobomyl acrylate, isobomyl methacrylate, methoxyethoxyethyl methacrylate, ethoxyethyl methacrylate, tetrahydrofurfuryl methacrylate, acetoxyethyl methacrylate, ethylene glycol dimethacrylate, diethylene glycol dimethacrylate, trimethylene glycol dimethacrylate, trimethylene glycol dimethacrylate, trimetholpropane trimethacrylate, 1,4-butanediol dimethacrylate, 1,6-hexanediol dimethacrylate, 1J2- dodecanediol dimethacrylate, propethylene glycol dimethacrylate, 2,2-bis[4'-(3"- methacryloyl-2"-hydroxypropoxy)phenyl]propane (bis-GMA), ethoxylated bisphenol A dimethyacrylate, 2,2-bis[4'-(3"-methacryloyl-2"-hydroxypropoxy)phenyl]propane (bis-GMA), ethoxylated bisphenol A dimethyacrylate, urethane dimethacrylate, methacryloyloxyethyl maleate and triethyleneglycol dimethacrylate, , pyromelhtic glycerol methacrylate, N-tolylglycine glycidyl methacrylate and mixtures thereof. A polymerization initiator is also included with the solvent. Examples include peroxy compounds such as benzoyl peroxide, cumene hydroperoxide and camphor qunione peroxide Another aspect of the present invention is directed to methods of pre- treating the buccal cavity and the teeth and surrounding soft tissue that are to receive a dental restorative composition or a dental prosthetic device. In general, about 40 percent of fillings have recurrent caries. Bacteria penetrate gaps, pits, fissures, cracks and other imperfections in the tooth created at the interface of the tooth and the filling material. The roughness of the tooth-filling interface also contributes to bacterial growth. The same phenomenon occurs in the case of caps or crowns. Thus, a preferred embodiment of this aspect entails a method for priming a dental surface to receive a dental reconstructive composition or prosthetic device. The tooth may have been drilled or otherwise prepared to have its surface altered to cleanse the cavity and better adapt the tooth to receive the composition or device. First, a dental primer is applied to the tooth or teeth. The primer contains a first anti-microbial agent and a volatile solvent in which the agent is soluble. When applied to the dental surface and when the solvent evaporates, a residue of the agent is left on the dental surface. The purpose of the primer is to make the tooth more receptive to the bonding agent by reducing the surface tension so that the bonding agent penetrates the crevices in the tooth. The solvent is allowed to evaporate. The dental adhesive composition is applied to the primed dental surface. The adhesive composition contains a bonding agent and a second anti-microbial agent, wherein the first and second anti-microbial agents may be the same or different. It is preferred that they are the same. The adhesive composition is allowed to harden thus leaving a residue of the antimicrobial agent and the bonding agent on the dental surface. The dental restorative composition or dental prosthetic device is then applied to the dental surface. The restorative composition or prosthetic device adheres to said dental surface and the anti-microbial agent inhibits microbial growth where composition or device forms an interface with the dental surface.

Typically, the dental restorative composition is a filling or material used to replace missing teeth. The dental prosthetic devices covers a tooth, and in some cases, the surrounding soft tissue as well. Examples of devices include crowns or caps, braces, retainers and dentures. In a less preferred embodiment, a dental restorative composition can be applied following treatment with only the primer. In another less preferred embodiment, a dental prosthetic device is applied following treatment with only the adhesive composition. EXAMPLE I

Ethanolic solutions containing triclosan were prepared as described in

Table 1.

Table I

Non carious teeth were extracted from an individual suffering from periodontal disease and stored in distilled water for 24 hours.' To determine the disinfective properties of the above solutions the teeth were not sterilized prior to use. The teeth were washed with 10 ml of distilled water and incubated in stimulated saliva for 5 minutes. The teeth were then air-dried and anti-microbial solutions (Solutions 1A and IB) were painted onto the surface of the teeth using a dental office brush, such as the brush sold under the name Benda Brush™ by Centrix (CT). . The teeth were then dried with a compressed air dental syringe for one minute in order to evaporate all of the alcohol. The teeth were placed onto Petri dishes containing a standard aqueous trypticase soy agar medium supplemented with sucrose. Control teeth were treated in the same fashion with water and a standard commercial cavity vamish sold under the name Copalite™ by Cooley & Cooley of Houston, Texas.

The Petri dishes were incubated at 37°C and the growth around the teeth was observed after 48 hours and 72 hours (photo not shown). The results are shown in Table 2.

Table 2

The data shown above indicate that the film produced prevents growth of the microorganisms on the tooth surface.

EXAMPLE 2

As in the case above, the teeth to be tested were extracted and stored in distilled water for 24 hours. The teeth were then removed and rinsed 3 times with 10 ml distilled water. The teeth were dried using a compressed air dental syringe, following with either 0J ml of water, Copalite™, Solution IA or Solution IB were painted onto the surface of the teeth using the Bend-A-Brush™ dental office brush. The teeth were then dried with a compressed air dental syringe for one minute in order to evaporate all of the alcohol, water, or Copalite™ solvent. The teeth were then placed onto standard aqueous trypticase soy agar supplemented with sucrose and inoculated with 0.25 ml of human saliva. The saliva was collected from an individual who, for the purposes of this test, did not brush for 12 hours.

The results showed significant zones of inhibition around teeth treated with Solutions 1 A and IB (photo not shown). Zones of inhibition were not observed around teeth treated with the controls. These results are shown in Table 3.

Table 3

The results shown in Table 3 indicate that a film of a water-insoluble anti microbial agent (triclosan) was deposited on a biological surface such as a tooth and its microbial inhibition effects observed in an aqueous surrounding medium.

EXAMPLE 3 Single-component, anti-microbial dental primer and adhesive compositions were prepared in accordance with this invention by dissolving triclosan in the same solvent used to deliver the adhesion-promoting agents to the tooth surface. The compositions shown in Table 4 are all visible light-cured, anti-microbial dental priming and/or bonding agents.

Table 4

INDUSTRIAL APPLICABILITY

The invention is useful in preventing bacterial infection at the interface of a biological system and a medical device. In particular, the invention is of use in preventing infection at the boundary between and around a dental restorative composition or dental reconstructive prosthesis (e.g., a crown or filling) and tooth enamel, dentin, root or gum tissue. The invention is useful in the adhesion of a dental reconstructive prosthesis to a dental surface under conditions that inhibit microbial growth at the interface between the prosthesis and the dental surface.

All publications cited in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All these publications are herein incorporated by reference to the same extent as if each individual publication were specifically and individually indicated to be incorporated by reference.

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as defined by the appended claims.

Claims

Claims:

I. A composition consisting essentially of an anti-microbial agent and a volatile solvent in which said agent is soluble, which when applied to a biological surface and when said solvent evaporates, leaves a residue of said agent. 2. The composition of claim 1 wherein said solvent is non- aqueous and said agent is water-insoluble.

3. The composition of claim 1 wherein said agent is non-cationic.

4. The composition of claim 1 wherein said agent is water- insoluble and non-cationic. 5. The composition of claim 4, wherein the anti-microbial agent is a halogenated salicylanilide.

6. The composition of claim 4 wherein the anti-microbial agent is a benzoic ester.

7. The composition of claim 4 wherein the anti-microbial agent is a halogenated carbanalide.

8. The composition of claim 4 wherein the anti-microbial agent is a phenolic compound.

9. The composition of claim 4 wherein anti-microbial agent is a halogenated diphenyl ether. 10. The composition of claim 9 wherein said halogenated diphenyl ether is triclosan.

I I. The composition of claim 10 wherein said triclosan is present in said composition in an amount of from about 0.1% to about 10% by weight of said composition. 12. The composition of claim 1 wherein said anti-microbial agent is present in said composition in an amount of from about 0.05% to about 30% by weight of said composition.

13. The composition of claim 1 wherein said solvent contains fewer than 12 carbon atoms.

14. The composition of claim 1 wherein said solvent is selected from the group consisting of an alcohol, a ketone, an aldehyde, an ester, an ether and mixtures thereof.

15. The composition of claim 1 wherein said solvent is ethanol. 16. The composition of claim 1 wherein said solvent is acetone.

17. The composition of claim 1 wherein said solvent is propionaldehyde.

18. The composition of claim 1 wherein said solvent is ethyl acetate. 19. The composition of claim 1 wherein said solvent is diethyl ether.

20. The composition of claim 1 wherein said solvent is an organosilane.

21. The composition of claim 20 wherein said organosilane is methacryloxypropyltrimethoxy silane.

22. The composition of claim 1 further consisting essentially of a film-forming polymer.

23. The composition of claim 22 wherein the said film forming polymer is selected from the group consisting of an acrylate polymer, a methacrylate polymer, a cellulose polymer, a polycarboxylate, a polyvinyl methyl ether/maleic polymer and combinations thereof.

24. A dental primer comprising an anti-microbial agent and a volatile solvent in which said agent is soluble, which when applied to a tooth and when said solvent evaporates, leaves a residue of said agent on said tooth. 25. The dental primer of claim 24 wherein said agent is water- insoluble.

26. The dental primer of claim 24 wherein said anti-microbial agent also possesses analgesic and/or anti-inflammatory activity.

27. The dental primer of claim 24 further comprising an analgesic.

28. The dental primer of claim 24 further comprising an anti- inflammatory agent.

29. The dental primer of claim 24 further comprising a film- forming polymer. 30. The dental primer of claim 29 wherein said film-forming polymer is selected from the group consisting of an acrylate polymer and a methacrylate polymer.

31. A dental adhesive composition comprising a water-insoluble anti-microbial agent and a dental adhesive. 32. The dental adhesive composition of claim 31 wherein said dental adhesive includes a bonding agent selected from the group consisting of urethane dimethacrylate, methacryloyloxyethyl maleate, triethyleneglycol dimethacrylate and bisphenol A-glycidyl methacrylate.

33. The dental adhesive composition of claim 31 further comprising a polymerizable solvent.

34. The dental adhesive composition of claim 33 wherein said polymerizable solvent is a methacrylate.

35. A method for priming a dental surface to receive a dental reconstructive composition or prosthetic device, comprising: a) applying to the dental surface a dental primer comprising an anti-microbial agent and a volatile solvent in which said agent is soluble, which when applied to the dental surface and when said solvent evaporates, leaves a residue of said agent on the dental surface; b) allowing said solvent to evaporate to produce a primed dental surface; and applying to the primed dental surface the dental reconstruction composition or prosthetic device.

36. The method of claim 35 wherein said dental reconstruction composition is a filling.

37. The method of claim 35 wherein said dental prosthetic device covers a tooth.

38. The method of claim 37 wherein said dental prosthetic device is a crown.

39. The method of claim 35 wherein said dental prosthetic device is a brace.

40. A method for priming a dental surface to receive a dental reconstructive composition or prosthetic device, comprising: a) applying to the dental surface a dental adhesive composition comprising a bonding agent and an anti-microbial agent, which when applied to the dental surface leaves a residue of said anti-microbial agent and said bonding agent on the dental surface; and applying to the dental surface the dental reconstruction composition or prosthetic device. 41. A method for applying a dental reconstructive composition or a dental prosthetic device to a dental surface, comprising:

(a) applying to the dental surface a dental primer composition comprising a first anti-microbial agent and a volatile solvent in which said agent is soluble, which when applied to the dental surface and when said solvent evaporates, leaves a residue of said anti-microbial agent on the dental surface; b) applying to the dental surface a dental adhesive composition comprising a bonding agent and a second anti-microbial agent, wherein said first and second anti-microbial agents may be the same or different, and allowing said dental adhesive composition to harden thus leaving a residue of said anti-microbial agent and said bonding agent on the dental surface; and c) applying to said dental surface the dental reconstructive composition or the dental prosthetic device.

42. A method of inhibiting microbial growth on a biological substrate, comprising applying the composition of claim 1 to the biological substrate.

43. The method of claim 42 wherein said biological substrate is skin.

44. The method of claim 42 wherein said biological substrate is ketatinous tissue. 45. The method of claim 42 wherein said biological substrate is dental tissue.

46. The method of claim 45 wherein said dental tissue is a tooth.