WO2010132126A1 - Flavored tooth-whitening composition in the form of a sustained release matrix - Google Patents

Abstract

A flavored tooth-whitening composition is provided for sustained release of a tooth-whitening oxidizing agent and a flavoring agent in the mouth.. The composition is composed of a soft solid matrix that provides sustained release of the whitening agent in the mouth throughout a time period of at least 15 minutes and up to 4 hours or more. The compositions, for example lozenges, may also include one or more additional beneficial agents. Exemplary beneficial agents include ionizable zinc compounds and other cold remedies, local anesthetics and anti-infective agents, diet aids, fluoride-releasing compounds, tooth re-mineralization agents, and tooth desensitization agents.

Description

FLAVORED TOOTH-WHITENING COMPOSITION IN THE FORM OF A SUSTAINED RELEASE MATRIX

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. provisional patent application Serial No. 61/178,447, titled "Flavored Tooth- Whitening Composition in the Form of a Sustained Release Matrix" filed May 14, 2009, the contents of which are incorporated herein in their entirety by reference.

TECHNICAL FIELD OF THE INVENTION

This invention relates generally to tooth whitening compositions, and more particularly relates to a solid matrix composition, such as a lozenge, that provides for sustained release of a tooth-whitening agent in the oral cavity.

BACKGROUND OF THE INVENTION

Yellowing, staining, and discoloration of the teeth are very common problems, occurring in the majority of adults. Teeth are composed of an outer layer of enamel, which contains virtually no organic material but is rather made up almost entirely of mineral components, primarily a crystalline calcium phosphate generally referred to as hydroxyapatite. This outer layer is hard but is nevertheless slightly permeable. The interior of the tooth, composed of "dentin," contains water as well as a significant fraction of organic materials — on the order of 20% or more — including collagen, glycoproteins, and proteoglycans, and is thus substantially softer than enamel. Dentin is necessary for the support of enamel, and is naturally yellow in color, thus it affects the color of the tooth since the outer enamel layer is somewhat translucent.

The natural color of the tooth is opaque to translucent white or slightly off-white. Staining of teeth arises as a result of exposure to tobacco products, coffee, tea, various foods, certain medications, and some bacterial pigments. Tannins and other polyphenols are particularly problematic with regard to staining. Compounds and materials that can stain the teeth can become trapped in or bound to the biofilm layer on the surface of the teeth, and can penetrate the enamel and even the dentin. Staining can also arise from sources within the teeth, for example from antibiotics such as tetracycline, if administered to an individual when young. Surface stains on the enamel can usually be removed, at least in part, by mechanical cleaning of the teeth. It is not possible to whiten discolored enamel or dentin in this way, however, and chemical or other methods (e.g., laser bleaching or application of white veneers) are necessary. Many types of products have been proposed for whitening teeth, and a variety of such products are now commercially available. There are, for instance, whitening toothpastes containing a bleaching agent, e.g., hydrogen peroxide and/or carbamide peroxide, etc.; a white pigment, e.g., titanium dioxide; other whiteners such as sodium bicarbonate (baking soda), or combinations of two or more of such agents. Examples of such toothpastes include Rembrandt® Plus Premium Whitening Toothpaste (McNeil-PPC, Inc.), Aquafresh® White and Shine (GlaxoSmithKline), and UltraBrite® (Colgate-Palmolive). See also U.S. Patent Nos. 6,682,717 to Wills et al., 6,432,388 to Alvarez-Hernandez, 6,132,702 to Witt et al., 5,041,280 to Smigel et al., all of which pertain to toothpastes containing one or more whitening agents.

Chewing gums containing tooth- whitening agents have also been available for some time. Commercially available products include Orbit White® chewing gum (Wrigley), which contains sodium bicarbonate, and Trident White® chewing gum (Cadbury Adams), which contains titanium dioxide. See also U.S. Patent No. 5,824,291 to Herman and 6,416,744 to Robinson et al.

Whitening toothpastes and whitening gums are popular, although their efficacy is limited. These products cannot contain high levels of whitening agents for a number of reasons, including taste. In addition, true bleaching agents such as hydrogen peroxide, organic peroxides, and peroxyacids would limit the types of possible formulation components that could be used and/or result in instability and a short shelf life, insofar as bleaching agents oxidize many organic components typically incorporated into such formulations. Another issue with these products, particularly with whitening toothpastes, is that the whitening agent remains in contact with the teeth for a very short period of time, only as long as a person chooses to brush his or her teeth. Similarly, whitening agents contained in mouthwash products sold as "whitening" mouthwashes would be in contact with the teeth for an even shorter period of time, significantly limiting the overall efficacy of the product.

To address some of these concerns, another class of tooth whitening products has been developed. With these products, the whitening agent is a bleaching agent (also referred to as an oxidizing agent) and is maintained in contact with the teeth for an extended time period. For instance, bioadhesive strips are available which are affixed to the teeth and allowed to remain in place for an hour or more, gradually releasing bleaching agent toward the surfaces of the teeth. There are also flexible "trays" that are designed to be filled with a whitening gel or viscous liquid and placed in position over the teeth, extending the amount of time that the bleaching agent(s) in the composition contacts the teeth. Such products include Crest Whitestrips® (Procter & Gamble), Rembrandt® Whitening Strips (J&J Healthcare), and Aquafiesh® White Trays (GlaxoSmithKline). These products are not particularly convenient, however; they interfere with eating and speaking, and can be uncomfortable when used for the time periods necessary to bring about a measurable whitening effect.

An ideal product would be a pleasant tasting lozenge or the like that could remain in the mouth for an extended time period and gradually release an effective tooth- whitening agent in the oral cavity. A product that would provide a substantially constant level of whitening agent at effective levels would be particularly desirable. Lozenges and other such products, however, are formulated with a plurality of organic components, many of which would be susceptible to being oxidized by a tooth-whitening bleaching agent. This would result in an unstable product with little or no shelf life. Furthermore, the most effective tooth-whitening agents — bleaching agents such as peroxides — require taste-masking and, therefore, have not been incorporated into a release system such as a lozenge, where there is contact with the taste buds, as they are located on the surface of the tongue. Lozenges are typically made from hard candy-type bases and dissolve in the mouth within a matter of a few minutes, limiting their capability as sustained release tooth-whitening systems.

SUMMARY OF THE INVENTION

It is therefore a primary object of the invention to provide a flavored tooth-whitening composition that overcomes the above-described disadvantages of other tooth- whitening products. The composition is in the form of a sustained release solid matrix, e.g., a soft lozenge, that gradually releases a tooth- whitening agent throughout a time period of 15 minutes to several hours, and, surprisingly, is stable and pleasant tasting despite the presence of up to 20 wt.% of a bleaching agent such as carbamide peroxide. Used properly, the composition is as effective as the popular commercially available tooth-whitening strips and tray products, but is far more convenient to use.

In one aspect, then, the invention relates to a flavored tooth- whitening composition in the form of a sustained release solid matrix, which provides for sustained release of a tooth- whitening oxidizing agent in the oral cavity throughout a time period of at least 15 minutes. In another aspect, the invention relates to a flavored tooth-whitening composition in the form of a soft, i.e., defoπnable, solid matrix unit, wherein the composition provides for sustained release of a tooth- whitening oxidizing agent in the oral cavity, wherein, following use of at least 24 of the units, e.g., lozenges, throughout a time period of less than one month, tooth whitening of at least one shade is achieved, where the term "shade" refers to a white color within the gradation of white, colors defined by the Vita Shade Guide. In most cases, whitening of at least four shades, and even at least seven shades, is observed. The degree of whitening that is achievable with any individual will, of course depend on several factors, e.g., the extent of tooth discoloration, the thickness of any yellowed coating, and the like.

In another aspect, the invention relates to a flavored tooth-whitening composition in the form of a soft, i.e., deformable, solid matrix unit, wherein the composition provides for sustained release of a tooth- whitening oxidizing agent in the oral cavity throughout a time period of at least 15 minutes, wherein, following use of at least 36 of the units, e.g., lozenges, throughout a time period of less than six weeks, tooth whitening of at least one shade, typically at least five shades, and optimally at least nine shades is achieved, with the above caveat regarding individual variability in results.

In still another aspect, the invention relates to a flavored tooth-whitening composition in the form of a soft, i.e., deformable, solid matrix unit, wherein the composition provides for sustained release of a tooth- whitening oxidizing agent in the oral cavity throughout a time period of at least 15 minutes, wherein, following use of at least 48 of the units throughout a time period of less than two months, tooth whitening of at least one shade, optimally at least seven shades, and optimally at least eleven shades is achieved, with, again, the above caveat regarding individual variability in results.

While not wishing to be bound by theory, the inventors herein propose that the surprisingly effective whitening achieved by the present solid matrix units may result from the high and substantially constant levels of whitening agent provided when the unit is retained in the oral cavity for at least 15 minutes. A high and substantially constant concentration of tooth- whitening agent at the surface of the teeth will oxidize surface stains, underlying dentin, plaque, and components of the biofilm that coats the interior surfaces of the mouth. To achieve the high concentration of whitening agent at the surface of the teeth, it is preferred that the lozenge or functionally equivalent solid matrix unit be manipulated within the mouth during use, ideally moved over the front surfaces of different teeth in succession.

In another aspect, the invention relates to a flavored tooth-whitening composition composed of a soft, solid matrix of a water-insoluble hydrophilic polymer, an essential oil component as a flavoring agent, and up to 20 wt.% of a tooth-whitening oxidizing agent. By an "essential oil component" is meant an essential oilier se or a component of an essential oil such as a terpene or sesquiterpene. Mixtures of essential oils and/or essential oil components are also contemplated. The term "water-insoluble" indicates that the solubility of the hydrophilic polymer in water is less than 5 wt.%, preferably less than 3 wt.%, more preferably less than 1 wt.% (measured at 20' ⁰C). The term "hydrophilic" is used in the conventional sense to indicate that the polymer has an octanol/water partition coefficient P of less than 1.0, preferably less than about 0.5. In the aqueous environment of the oral cavity, the matrix gradually releases the flavoring agent and the tooth- whitening agent throughout a time period of at least 15 minutes. The essential oil component penetrates into the otherwise hard polymeric matrix, thus acting as a plasticizing agent, i.e., increasing the plasticity or fluidity of the otherwise hard matrix such that a soft, deformable lozenge is provided.

In a further aspect, the invention relates to a flavored tooth-whitening composition that provides for sustained release of a tooth-whitening oxidizing agent as above, and that further contains one or more beneficial agents, wherein the composition provides for sustained release of the beneficial agent(s) as well. The invention is not limited with respect to the beneficial agent, with the proviso that the agent should be pharmaceutically acceptable and inert with respect to other components of the composition. Exemplary beneficial agents, however, include cold remedies, agents for combating halitosis, local anesthetics and anti-infective agents, diet aids, fluoride-releasing compounds, tooth remineralization agents, tooth desensitization agents, other agents exhibiting utility in the dental context, and nicotine.

In an additional aspect of the invention, the sustained release matrix, composed of a water-insoluble, hydrophilic polymer, an essential oil component, and the tooth-whitening oxidizing agent, is incorporated into a chewing gum base, such that the composition is a chewing gum that provides for sustained release of the whitening agent. In addition to the aforementioned components, one or more additional beneficial agents may, if desired, be incorporated into the chewing gum as well. In a further aspect of the invention, the whitening composition may be rendered either adhesive or nonadhesive by varying the molecular weight of the hydrophilic polymer, and/or by incorporating an ingestible solvent such as ethanol or ethyl lactate into the lozenge formulation, and/or by incorporating one or more bioadhesive polymers into the composition. A lower molecular weight hydrophilic polymer will give rise to a sticky, pliable solid matrix unit that can adhere to the gum, teeth, or dental appliance, while a higher molecular weight hydrophilic polymer will give rise to a soft, rubbery solid matrix unit that is substantially nontacky. Incorporation of an ingestible solvent such as ethanol or ethyl lactate can further increase adhesion.

In another aspect of the invention, a method is provided for using the presently disclosed tooth-whitening composition to whiten the teeth. The individual desiring whiter teeth uses one to four whitening units per day, preferably one or two per day, until an acceptable degree of tooth whitening is achieved. This will typically require one to two months, and whitening of at least several shades can usually be achieved. As noted above, the user should manipulate the whitening unit within the mouth so that the front surfaces of individual teeth are contacted. After the desired degree of whiteness is achieved, one to four units per day should be used over at least a one to two week period, to maintain the desired degree of whiteness.

In yet another aspect of the invention, a method is provided for making the tooth- whitening composition disclosed herein. The method is straightforward, employs a commercial mixing device, and is carried out in air at room temperature. Accordingly, the method may readily be scaled up to the industrial manufacturing level.

A representative composition of the invention is composed of a lozenge in the form of a soft matrix that comprises a mixture of ethylcellulose having a solution viscosity in the range of approximately 90 to 100 cP as determined at 25 ⁰C using a 5 wt.% aqueous solution, a flavoring agent selected from essential oils, individual terpenes, and individual sesquiterpenes, i.e., an essential oil component as defined above, an ionizable zinc compound, a binder, a disintegrant, and a nonrsugar sweetening agent, wherein the weight ratio of the ethylcellulose to the essential oil component is in the range of approximately 1:1.5 to 1.5:1. The binder is selected to provide cohesive strength to the lozenge or the like, while the disintegrant facilitates gradual disintegration in the oral cavity. Preferred compositions of the invention are not only pleasantly flavored but also generally comfortable to retain in the mouth for an extended period of time, primarily by virtue of the matrix units' small size and soft, rubbery consistency. Sustained release of a powerful flavoring agent provides for extremely effective taste-masking of the tooth- whitening oxidizing agent and any other bitter or otherwise unpleasant-tasting components, and the composition can therefore be used to deliver a host of beneficial agents whose bitter or otherwise unpleasant taste has prevented administration in lozenge or analogous form, along with the tooth whitening agent.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the results of a pilot study on a product of the invention.

FIG. 2 depicts a projection of the pilot study results to a greater number of lozenges.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Nomenclature:

Unless otherwise indicated, the invention is not limited to specific compositional forms, formulation components, tooth-whitening agents, or methods of use of manufacture, as such may vary. It is also to be understood that the terminology used herein is fpr the purpose of describing particular embodiments only and is not intended to be limiting.

As used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a polymer" includes a single polymer as well as two or more polymers in combination, reference to "a flavoring agent" or "a whitening agent" encompasses a combination or mixture of different flavoring agents or whitening agents as well as a single flavoring agent or whitening agent, and the like.

In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings:

"Optional" or "optionally present" - as in an "optional additive" or an "optionally present additive" means that the subsequently described component (e.g., additive) may or may not be present, so that the description includes instances where the component is present and instances where it is not. By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a composition of the invention without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the lozenge formulation. The term "biocompatible" is used interchangeably with the term "pharmaceutically acceptable." When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical excipient, it is implied that the excipient has met the required standards of toxicological and manufacturing testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

The term "beneficial agent" refers to any chemical compound, complex or composition that exhibits a beneficial effect, e.g., a prophylactic or therapeutic effect in the prevention or treatment of an adverse physiological condition, respectively. The term also encompasses pharmaceutically acceptable derivatives of those beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, analogs, and the like. When the term "beneficial agent" is used, then, or when a particular beneficial agent is specifically identified, it is to be understood that pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, active metabolites, isomers, analogs, etc. of the beneficial agent are intended as well as the beneficial agent per se.

By an "effective" amount of a beneficial agent is meant a nontoxic but sufficient amount of the agent to provide the desired effect. The amount of beneficial agent that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the particular active agent or agents, and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation

The terms "hydrophilic" and "hydrophobic" are generally defined in terms of a partition coefficient P, which is the ratio of the equilibrium concentration of a compound in an organic phase to that in an aqueous phase. A hydrophilic compound has a P value less than 1.0, typically less than about 0.5, where P is the partition coefficient of the compound between octanol and water, while hydrophobic compounds will generally have a P greater than about 1.0, typically greater than about 5.0. The term "water-insoluble" refers to a compound or composition whose solubility in water is less than 5 wt.%, preferably less than 3 wt.%, more preferably less than 1 wt.%, while the term "water-soluble" refers to a compound or composition whose solubility in water is greater than or equal to 5 wt.%, preferably greater than 10 wt.%, more preferably greater than 15 wt.% (measured in water at 20 ⁰C).

The term "lozenge" is sometimes used herein to refer to individual solid matrix tooth- whitening units. It should be understood, however, that the term does not restrict the shape or size of the unit. In addition, it is intended that the term "unit," and the term "lozenge," unless otherwise indicated, can encompass compositions with a chewing gum base as well as units affixed to a support to be handled and manipulated from a location external to the mouth, e.g., as is the case with a lollipop, pen-type whitening system, or the like.

Accordingly, the invention provides a flavored tooth-whitening composition in the form of solid matrix units for sustained release of a tooth- whitening oxidizing agent in the oral cavity, preferably sustained release throughout an extended time period in the range of about 15 minutes to 4 hours or more, typically in the range of about 15 minutes to 2 hours or more, and most typically in the range of about 15 minutes to about 60 minutes. In one embodiment, the composition comprises a soft matrix unit of a water-insoluble hydrophilic polymer, e.g., ethylcellulose, an essential oil component to serve as a flavoring agent and plasticize the polymer (thereby forming the soft matrix), and a tooth-whitening oxidizing agent. Preferred lozenges and other compositional units of the invention do not dissolve within the mouth, but very gradually disintegrate as the whitening agent, flavoring agent, and optionally present additional beneficial agents are released. Following release of the majority of these agents, the remainder of the composition undergoes degradation into small fragments that may or may not be swallowed, insofar as the entire compositional unit is composed of biocompatible, nontoxic components.

The length of time that the composition can be retained in the mouth and provide sustained release is controlled in part by the appropriate selection of hydrophilic polymer and flavoring agent, and in part by the relative amounts of the hydrophilic polymer and the flavoring agent. In general, the weight ratio of the hydrophilic polymer to the flavoring agent should be in the range of approximately 1 :5 to 2:1, preferably in the range of approximately 1:2 to 1.5:1, and optimally in the range of approximately 1 : 1.5 to 1.2: 1. A higher ratio of flavoring agent to polymer may provide a matrix that may be too sticky for some of the present purposes, while a lower ratio may result in a composition that is not sufficiently cohesive to provide the desired matrix, depending on the polymer and on other components of the composition. Accordingly, the aforementioned ratios are not intended to be limiting, however, and ratios outside of the recited ranges may be desirable to provide a different type of composition, e.g., compositions having a particularly soft consistency or a tendency to degrade more quickly.

Otherwise, the fraction of each component in the composition is not particularly important, although, typically, the hydrophilic polymer and the flavoring agent each represents about 15 wt.% to about 40 wt.% of the composition, preferably in the range of about 15 wt.% to about 30 wt.% of the composition, more preferably in the range of about 20 wt.% to about 30 wt.% of the composition, and optimally in the range of about 22 wt.% to about 25 wt.% of the composition, while the tooth-whitening oxidizing agent is present in an amount in the range of about 5 wt.% to about 20 wt.%, preferably about 7.5 wt.% to about 17.5 wt.%, and most typically in the range of about 10 wt.% to about 15 wt.%, and optimally about 12 wt.%. Other components that may be incorporated into the composition, and their respective preferred amounts, are described infra.

Whitening Composition Components:

The polymer component of the composition is water-insoluble and biocompatible as those terms are defined herein. That is, the polymer component has: an octanol-water partition coefficient P of less than 1.0, preferably less than 0.5; a solubility in water of less than 5 wt.%, preferably less than 3 wt.%, most preferably less than 1 wt.% at 0⁰C; and does not give rise to undesirable biological effects or interact in an adverse manner with any of the other components of the composition. Preferred polymers within this group may be identified by wetting a candidate polymer with an essential oil component such as an essential oil per se to form a wet polymer matrix, compressing the wet matrix (such that the polymer actually dissolves to a very limited extent in the essential oil component), and noting the consistency of the compressed matrix. Ideal polymers result in a compressed wet matrix that has a rubbery consistency and exhibits both physical integrity and some degree of porosity.

Varying the molecular weight or viscosity of the polymer in a composition of the invention can impart certain properties to the lozenge or other compositional unit. More specifically, a lower molecular weight polymer (e.g., ethylcellulose having a solution viscosity of about 6 to 15 cP) can give rise to a pliable, sticky product, as alluded to in the preceding section, while a higher molecular weight polymer can provide a soft, rubbery, and nontacky composition. Molecular weight also impacts on release rate and time to disintegration in the mouth, i.e., on the rate at which the tόoth-whitening oxidizing agent and other components in the composition are released, and on the time the lozenge remains intact, respectively. With a chewing gum, for example, a higher molecular weight polymer results in a gum that lasts longer than a gum prepared with a lower molecular weight polymer but that is otherwise identical. With lozenges and the like, use of a higher molecular weight polymer, as compared to a lower molecular weight polymer, tends to give rise to a product that exhibits more rapid release kinetics and more rapid breakdown, given equivalent quantities of other components present. It should be noted that using a lower molecular weight polymer enables the incorporation of a smaller fraction of the essential oil component without reducing the overall strength of the matrix.

The particle size of the polymer is also relevant to the properties of the tooth- whitening composition, e.g., lozenge, made therewith. Generally, the polymers useful in conjunction with the invention have a particle size in the range of about 1 micron to about 250 microns. Micronized polymers, e,g., micronized ethylcellulose, are preferred for formation of strong polymer matrix systems, while matrices manufactured with polymers having a larger particle size tend to break apart faster. Micronized polymers generally have a particle size of less than 75 microns. For the present purpose, an exemplary cellulosic polymer is ethylcellulose. The ethylcellulose should have a solution viscosity in the range of approximately 5 to 150 cP, with a preferred solution viscosity in the range of approximately 50 to 125 cP, and a most preferred solution viscosity in the range of approximately 90 to 110 cP. The ethoxyl content is typically in the range of about 45.0% to 52.0%, preferably in the range of about 48.0-49.5%. Ideally, the polymer should also have a small particle size, with, for instance, a mean particle size in the range of about 10-90 microns, preferably 30-60 microns. Suitable ethylcellulose polymers that are available commercially include, without limitation, those that may be obtained from the Dow Chemical Company (Midland, MI) as ETHOCEL^® ethylcellulose, e.g., ETHOCEL^® Standard 4 Premium (solution viscosity range approximately 3 to 5.5 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 7 Premium (solution viscosity range approximately 6 to 8 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 10 Premium (solution viscosity range approximately 9 to 11 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 14 Premium (solution viscosity range approximately 12.6 to 15.4 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 20 Premium (solution viscosity range approximately 18 to 22 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 45 Premium (solution viscosity range approximately 41 to 49 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Standard 100 Premium (solution viscosity range approximately 90 to 110 cP, ethoxyl content 48.0-49.5%), ETHOCEL^® Medium 50 (solution viscosity range approximately 43 to 55 cP, ethoxyl content 45.0-47.0%), ETHOGEL^® Medium 70 (solution viscosity range approximately 63 to 85 cP, ethoxyl content 45.0-47.0%), ETHOCEL^® Medium 100 (solution viscosity range approximately 90 to 110 cP, ethoxyl content 45.0-47.0%), ETHOCEL^® HE 10 (solution viscosity range approximately 9 to 11 cP, ethoxyl content 49.5-52.0%), with all solution viscosities determined using an Ubbelohde viscometer and a solvent mixture of 80% toluene and 20% alcohol. A particularly preferred polymer herein is ETHOCEL^® 100 FP (solution viscosity range approximately 90 to 100 cP, ethoxyl content 48.0-49.5%, mean particle size 30-60 microns, maximum particle size 150 microns).

Other water-insoluble hydrophilic polymers may also be used, providing that the polymer or polymers can be plasticized with an essential oil or constituent thereof to give the desired sustained release matrix that has a soft, "wet" feel. Preferred polymers are also micronized with mean and maximum particle size akin to those of ETHOCEL^® 100 FP. Copolymers, terpolymers, etc. (including random copolymers, block copolymers, graft copolymers, and the like), are contemplated in addition to homopolymers, as are different three- dimensional polymeric forms, e.g., linear, branched, dendrimeric, star, etc. Crosslinked polymers are less preferred, but lightly crosslinked polymers are acceptable providing that they may be plasticized with an essential oil or constituent thereof to give a matrix with the desired softness and sustained release properties. The polymers may be synthetic, naturally occurring, or modified naturally occurring polymers, with chemically synthesized polymers having the identical structure of naturally occurring polymers also included. In addition to ethylcellulose, then, the following polymers are a few examples of those that may be used herein: cellulose ethers in addition to ethylcellulose, with varying degrees of substitution, and copolymers and derivatized forms thereof, e.g., methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), ethyl-HEC copolymer (EHEC), methyl-ethyl-HEC (MEHEC), etc.; polyalkylene oxides, particularly polyethylene oxide and poly(ethylene oxide - co - propylene oxide); polyoxyalkylated sugars such as polyoxyethylated sorbitol and polyoxyethylated glucose; poly(olefinic alcohols) such as poly(vinyl alcohol) derivatized to reduce water solubility; poly(N-vinyl lactams) such as polyvinyl pyrrolidone) and poly(N-vinyl caprolactam); polyvinyl amines; and the like. Polymer blends are also possible.

Many essential oils and essential oil components are available and suitable as flavoring agents herein. Flavoring agents may be combined, if desired, to produce a particular flavor mix. Preferred flavoring agents are those that plasticize the water-insoluble hydrophilic polymer, i.e., agents that upon admixture with the hydrophilic polymer result in a soft, wet matrix that, in the aqueous environment of the mouth, gradually releases the flavoring agent and any other incorporated component. By a "wet" matrix is meant a matrix that contains a liquid phase that represents a sufficiently large fraction of the matrix to provide a discernibly wet or sticky surface, and/or a soft and rubbery consistency. Ideal flavoring agents in this regard are pharmaceutically acceptable essential oils and chemical constituents of essential oils that can impart a desired flavor. Essential oils, as known in the art, are naturally occurring compounds or compositions that accumulate in the oil cells, glandular trichomes, and oil or resin ducts of aromatic plants.

Essential oils that can be incorporated into the present whitening compositions as suitable fiavoring/plasticizing agents include, without limitation, citrus oils such as lemon oil, lime oil, neroli oil, and orange oil, mint oils such as peppermint oil and spearmint oil, and other oils such as anise oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eriodictyon fluidextract, eucalyptus oil, fennel oil, glycyrrhiza extract, lemongrass oil, and nutmeg oil. The citrus and mint oils are generally preferred, and mint oils are particularly effective in taste- masking tooth-whitening oxidizing agents such as hydrogen peroxide and carbamide peroxide.

As is widely appreciated in the art, essential oils contain a number of constituents, many of which can by themselves serve as flavoring agents. Of these, the most well-known essential oil constituents that are widely used as flavoring agents are hydrocarbons, particularly terpenes and sesquiterpenes. "Terpenes" generally refer to hydrocarbons of the formula CtoHiβ, and, as the term is used herein, also encompass terpene analogs of the formula C_nH_2M, as well as terpenes and terpene analogs substituted with one or more nonhydrogen substituents and/or containing a heteroatom such as N, O, or S. Analogously, "sesquiterpenes" generally refer to hydrocarbons of the formula C15H24, but for the purpose of the present invention also encompass sesquiterpene analogs of the formula C_nH_2n-O as well as substituted and/or heteroatom-containing derivatives thereof.

It will be appreciated from the foregoing definitions that terpenes and sesquiterpenes can have any number of molecular structures, including acyclic, monocyclic, bicyclic, and polycyclic structures, wherein the bicyclic and polycyclic structures may or may not be "bridged" bicyclic and polycyclic compounds. In general, however, the terpenes that are more commonly used as flavoring agents contain two double bonds and one cyclic group (e.g., β- phellandrene) or one double bond and two cyclic groups in a bridged bicyclic structure (e.g., β- pinene). Specific examples of terpenes and sesquiterpenes that can be advantageously used as flavoring agents herein include: the terpenes dJ-camphene, c?-camphene, /-camphene, Δ³-carene, /rαλu-β-ocimene, cw-β-ocimene, frατ«-α-ocimene, c/s-α-ocimene, β-pinene, β-phellandrene, α- terpinene, β-terpinene, and γ-terpinene; and the sesquiterpenes α-cadinene, β-cadinene, α- caryophyllene, copaene, β-farnesene, isocaryophyllene, and ylangene.

In addition to the terpenes and sesquiterpenes, essential oils contain a number of other types of constituents that may also serve as flavoring agents, either individually or in combination. These include, by way of example: organic acids such as/j-anisic acid, cinnamic acid, and phenylacetic acid; alcohols, including phenols, such as ^/-borneol, rf-borneol, /-borneol, carvacrol, chavicol, cinnamyl alcohol, linalool, menthol, nerolidol, nerol, d'J-α-terpineol, rf-α-terpineol, l-a- terpineol, and thymol; aldehydes such as acetaldehyde, anisaldehyde, cinnamaldehyde, benzaldehyde, citral, isovaleric aldehyde, piperonal, salicylaldehyde, valeric aldehyde, and vanillin; ketones such as carvone, jasmone, menthone, and piperitone; esters such as amyl acetate, bornyl acetate, benzyl benzoate, butyl cinnamate, cinnamyl anthranilate, geranyl acetate, linalyl acetate, menthyl acetate, menthyl isovalerate, and methyl salicylate; and phenol ethers such as anethole, eugenol, safrol, and estragole. The amount of flavoring agent used can be varied in order regulate the strength of the polymeric matrix prepared. Higher levels of the essential oil, essential oil component (e.g., terpene), or the like relative to the matrix polymer will give rise to a stronger, more cohesive matrix and thus a slower release rate.

The tooth-whitening agent herein is a bleaching agent, i.e., an oxidizing agent. Such agents oxidize stains present on the enamel of the teeth and, upon prolonged and/or repeated exposure of the teeth to oxidizing agents, will permeate through the enamel and into dentin, reducing discoloration in the interior of the teeth that is visible through the somewhat translucent enamel.

Examples of tooth- whitening oxidizing agents useful in connection with the present invention include, without limitation, peroxides, chlorites, perborates, percarbonates, persulfates, peroxyacids, and combinations thereof. Suitable peroxide compounds include: hydrogen peroxide; organic peroxides, including carbamide peroxide (urea peroxide), dialkyl peroxides such as di(t-butyl) peroxide and 2,2-bis(t-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as t-butyl perbenzoate and t-butyl per-2- ethylhexanoate, ketone peroxides such as cyclohexanone peroxide and methylethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and t-butyl hydroperoxide; and metal peroxides. Chlorites useful as oxidizing agents herein are typically metal chlorites, e.g., calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite. Hypochlorites and chlorine dioxide may also be used. Examples of perborates useful herein are perborate monohydrates and tetrahydrates, examples of suitable percarbonates include sodium percarbonate, potassium percarbonate, diacetyl peroxydicarbonate, and dicyclohexyl peroxydicarbonate, and examples of suitable persulfates include potassium, ammonium, sodium, and lithium persulfates. Peroxyacids useful as oxidizing agents herein include peracetic acid, peroxydiphosphoric acid, and peroxydisulfuric acid. Preferred whitening agents herein are peroxides, particularly hydrogen peroxide and organic peroxides such as carbamide peroxide.

In addition to containing one or more whitening agents of the aforementioned class, the tooth- whitening compositions herein may contain at least one additional type of whitening agent, referred to herein as a "secondary whitening agent." Such additional types of whitening agents include, without limitation, anti-tartar (anti-calculus)agents, including phosphates such as pyrophosphates, polyphosphates, polyphosphonates (e.g., ethane- 1 -hydroxy- 1,1-diphosphonate, l-azacycloheptane-ljl-diphosphonate, and linear alkyl diphosphonates), and salts thereof; linear caxboxylic acids; sodium zinc citrate; and mixtures thereof. Preferred pyrophosphate salts are the dialkali metal pyrophosphate salts, tetra-alkali metal pyrophosphate salts; and the hydrated or unhydrated forms of disodium dihydrogen pyrophosphate (NaH₂P₂O?), tetrasodium pyrophosphate (Na₄P₂Oy), and tetrapotassium pyrophosphate (K4P.2O7). The pyrophosphate salts are described in more detail in Kirk & Othmer, Encyclopedia of Clinical Technology Third Edition, Volume 17, Wiley-Interscience Publishers (1982). Additional whitening agents that can be incorporated into the present composition may also include tartar dissolving agents such as betaines, amine oxides and quaternaries, as described in U.S. Pat. No. 6,315,991 to Zofchak.

Enzymatic agents that would act to inhibit the formation of plaque, calculus or dental caries can also serve as secondary whitening agents herein. Suitable such agents include proteases that digest salivary proteins in the biofilm of the oral cavity and which are also absorbed onto the surface of the teeth. Other suitable enzymes include lipases that destroy ■bacteria by lysing proteins and lipids that form the structural component of bacterial cell walls and membranes; dextranases, glucanohydrolases, endoglycosidases, and mucinases, which break down the bacterial skeletal structure that forms a matrix for bacterial adhesion to the teeth; and amylases, which prevent the development of calculus by cleaving and digesting the carbohydrate-protein complex that binds calcium. Of course, any enzymatic agent that is employed must be compatible with other components of the formulation and not adversely interact therewith, particularly with respect to the tooth-whitening oxidizing agents.

Whiteness-imparting particles can also serve as secondary whitening agents, provided that they do not adversely interact with the primary whitening agent, the oxidizing agent. These particles can be any white colored or white pigmented particles, such as white polymer particles, white mineral particles, pearlescent particles, and the like. Amorphous calcium phosphate is a particularly preferred whiteness-imparting particle, insofar as tooth remineralization is also promoted. Whiteness-imparting polymeric particles can be selected, for instance, from those described in U.S. Patent No. 6,669,930 to Hoic, incorporated by reference herein. Whiteness- imparting pearlescent particles include, by way of example, those described in U.S. Patent No. 7,118,732 to Ibrahim et al., also incorporated by reference herein. In order to enhance the taste of the composition, at least one sweetener is preferably incorporated into the formulation. The sweetener may be a sugar, e.g., sucrose, fructose, or dextrose, or, more preferably, a non-sugar sweetening agent to reduce both caloric intake and the likelihood of dental caries. Sweeteners falling within the latter group include many well known artificial sweetening agents, such as, for instance, aspartame, saccharin, saccharin salts (e.g., sodium saccharin, calcium saccharin), sucralose, acesulfame-K (potassium acetosulfam), sorbitol, xylitol, stevioside, steviol, mannitol, erythritol, lactitol, alitame, miraculin, monellin, and thaumatin. In compositions of the invention, the sweetener is generally incorporated within the wet matrix, i.e., physically entrapped therein, while with chewing gums, this is not generally the case. That is, with gums, although the sweetener and the wet matrix may be intimately mixed, the sweetener is not entrapped within the gum (although this tends to result in quicker release of the sweetener from a gum than a lozenge, the release of the flavoring agent is gradual in preferred formulations of the invention, as is release of the tooth-whitening oxidizing agent).

It is preferred that tooth- whitening lozenges and other compositional units of the invention contain about 5 wt.% to about 15 wt.% of at least one binder. Binders, as is known in the art, are selected to provide cohesiveness to a composition, ensuring that a lozenge, dosage form, etc. remain intact after preparation. Preferred binders useful herein include, without limitation, gums such as gum arabic (acacia), guar gum, and sodium alginate; starch; gelatin; waxes; pectins; sugars such as sucrose, glucose, dextrose, molasses, and lactose; polyethylene glycol; hydrophilic polymers such as acrylic acid polymers and copolymers thereof, e.g., those known as carbomers (Carbopol®, B. F. Goodrich, is one such polymer), polyvinyl alcohol, polyvinylpyrrolidone; and cellulosic polymers such as hydroxypropyl methylcellulose (e.g., Methocel®, which may be obtained from the Dow Chemical Company), hydroxypropyl cellulose (e.g., Klucelφ, which may also be obtained from Dow), hydroxypropyl cellulose ethers (see, e.g., U.S. Patent No. 4,704,285 to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, and the like. Particularly preferred binders herein include gum arabic and guar gum.

It is additionally preferred that the composition contain about 5 wt.% to about 15 wt.% of at least one disintegrant selected to facilitate a steady, gradual, and smooth process by which the lozenge disintegrates in the mouth, releasing the tooth-whitening oxidizing agent, the flavoring agent, etc. A preferred disintegrant is xanthan gum; other suitable disintegrants include polyvinyl pyrrolidone, sodium starch glycolate, crosslinked sodium carboxymethyl cellulose (croscarmellose). It should be noted that some compounds can serve as both binders and disintegrants, e.g., xanthan gum, such that the compound enhances cohesive strength while also ensuring that the disintegration process is steady and gradual.

The compositional units, e.g., lozenges, optionally contain a colorant and/or other conventional additives as well. With respect to colorants, some essential oils are already colored and the color so provided may be acceptable. For example, peppermint oil imparts a yellow color, while cinnamon oil imparts a brown color. Without an added colorant, and in the absence of a colored flavoring agent, the lozenges, gums, etc. of the present invention will tend to be off- white or slightly darker, and may have some degree of translucence. Accordingly, a colorant may be added if a colored lozenge or the like is desired. Suitable colorants include natural colorants, i.e., pigments and dyes obtained from mineral, plant, and animal sources. Examples of natural colorants include red ferric oxide, yellow ferric oxide, annattenes, alizarin, indigo, rutin, and quercetin. Synthetic colorants may also be used, and will typically be an FD&C or D&C dye, e.g., an approved dye selected from the so-called "coal-tar" dyes, such as a nitroso dye, a nitro dye, an azo dye, an oxazine, a thiazine, a pyrazolone, a xanthene, an indigoid, an anthraquinone, an acridine, a rosaniline, aphthalein, a quinoline, or a "lake" thereof, i.e., an aluminum or calcium salt thereof. Particularly preferred colorants are food colorants in the "GRAS" (Generally Regarded As Safe) category.

Other additives can be incorporated into the present formulations, provided that they are biocompatible, pharmaceutically acceptable, and do not adversely interact with any other components of the composition. For instance, compounds that would be oxidized to any measurable extent by the tooth-whitening oxidizing agent, e.g., hydrogen peroxide or carbamide peroxide, would be unacceptable to incorporate into the present formulations unless a reduction in the amount of oxidizing agent used would eliminate the problem without compromising whitening efficacy. With the aforementioned caveat, suitable additives include, without limitation: release rate modifiers, particularly release rate accelerants that also serve as softening agents, such as water-soluble polymers (e.g., MC, HPC, HPMC, etc.); adhesion modifiers (including adhesion-increasing agents and adhesion-reducing agents) such as ingestible solvents (e.g., ethyl acetate and ethanol increase tack when admixed with ethylcellulose), mineral oil and vegetable oils (which tend to decrease tack when admixed with ethylcellulose), and additional polymers and polymer compositions, including polymers typically used to form hydrogels, e.g., ethylene vinyl acetate, polyvinyl alcohol, polyvinyl pyrrolidone, cellulose acetate, cellulose diacetate, and other cellulose esters, which may increase or decrease tack depending on the particular polymer or polymer composition; flavor stabilizers (e.g., starches); flavor diluents (e.g., ingestible solvents, as above); pH-adjusting agents (e.g., acids, bases, buffer systems); preservatiyes (e.g., antioxidants, antimicrobial agents, etc.); lubricants; and fillers (e.g., maltodextrin, microcrystalline cellulose, lactose, mannitol, etc.). It will be appreciated that certain compounds can serve at least one purpose; for example, an ingestible solvent can serve as both a release rate modifier and flavor diluent. hi addition to the flavoring agent, the formulation may also include one or more beneficial agents that are released within the mouth. Compositions of the invention will provide for sustained release of additional beneficial agents because the agents are incorporated within the wet matrix composed of the hydrophilic polymer and the essential oil component. With gums, release of an added beneficial agent may or may not be gradual, since the added agent will generally not be incorporated into the aforementioned wet matrix; rather, the release profile will depend on factors such as the nature of the agent(s), the tendency of the agent to remain in the gum (i.e., the physical/chemical attraction of the agent to one or more components of the gum), and the presence of one or more sustained release polymers.

The appropriate amount of any beneficial agent in the tooth- whitening composition will depend on the particular agent and the intended daily dose, and presumes that one to four, generally one or two, lozenges or other compositional units will be consumed on a daily basis. Unless explicitly indicated herein, it is to be understood that appropriate daily doses for the various agents will be known to those of ordinary skill in the art of pharmaceutical formulation and pharmacology and/or can be found in the pertinent texts and literature. The beneficial agent may be administered to provide a local, topical effect, within the oral cavity (e.g., as a topical anti-infective or anesthetic), or to achieve a systemic effect by passing through the mucosal membranes within the oral cavity and into an individual's blood stream, with the former preferred. Preferably, any added beneficial agent is intended to provide a local effect within the mouth. Examples of beneficial agents that may be incorporated into the present tooth- whitening compositions may be selected from any of the various classes of such agents including, but not limited to, analgesic agents, anesthetic agents (including local anesthetic agents for numbing a painful region within the mouth), anti-inflammatory agents, antimicrobial agents (including local antibiotics for treatment of an infection of the gum or elsewhere within the oral cavity), antiviral agents, cough and cold preparations, diet aids, nicotine, nutritional agents, such as vitamins, essential amino acids, and fatty acids; tooth remineralization agents such as amorphous calcium phosphate, calcium fluoride, and other calcium compounds and fluoride-releasing agents; and tooth desensitization agents which mitigate against sensitivity that may otherwise result from use of tooth- whitening oxidizing agents and/or other causes, e.g., potassium nitrate, strontium chloride, sodium fluoride, stannous fluoride, etc.; and combinations thereof.

Any of the aforementioned active agents may incorporated into the composition provided that they are biocompatible and will not adversely interact with any other components of the composition, e.g., the tooth-whitening oxidizing agent. Beneficial agents administered in combination may be from the same therapeutic class (e.g., two different vitamins) or from different therapeutic classes (e.g., an antibiotic and an anti-inflammatory agent). Some agents, as will be appreciated by those of ordinary skill in the art, are encompassed by two or more of the aforementioned groups.

Compositions of the invention are well-suited to administer beneficial agents whose efficacy increases as a result of an extended residence time in the oral cavity, which results in greater oral mucosal absorption of any particular agent. Such agents include, by way of example: coenzyme QlO and xylitol, in the treatment of periodontal disease and/or adverse systemic conditions; aspirin and nonsteroidal anti-inflammatory agents; opioid analgesics and other medications which the stomach may not tolerate (and, therefore, have had to be administered rectally or via some other relatively inconvenient non-oral route of administration); and allergy medications for rapid relief of allergic symptoms (e.g., diphenhydramine). Beneficial agents of particular interest herein are cold remedies, agents for combating halitosis, local anesthetics, local anti-infective agents, fluoride-releasing compounds and other agents exhibiting utility in the dental context, and nicotine.

Cold remedies include, but are not limited to: sources of Zn²⁺, i.e., ionizable zinc compounds; vitamins, including vitamin C optionally combined with one or more B vitamins; and herbal extracts such as echinacea and golden seal.

Ionizable zinc compounds are useful for reducing the duration and/or symptoms of common colds, managing upper respiratory allergy, as nutritional agents, and in treating halitosis, i.e., for reducing or eliminating bad breath. The ionizable zinc compound may be an inorganic or organic complex; examples of suitable complexes include zinc gluconate, acetate, chloride, propionate, butyrate, n-butyrate, beta-hydroxybutyrate, benzoate, formate, and sulfate, although zinc acetate and gluconate are generally preferred for reasons of stability, acidity in an aqueous environment (and thus potential toxicity), and suitability for sustained release in the present formulations. In this embodiment, lozenges are preferred to gums, so as to maximize the time period during which the zinc compound is released. The soft matrix of the present formulations, which provides for gradual release of the tooth- whitening agent and the flavoring agent in the mouth, also serves to minimize the unpleasant, bitter taste of many zinc-containing compounds. In addition, conventional zinc lozenges last only minutes, so that the availability of zinc in the mouth is limited, which correspondingly limits the capability of the zinc to exert a maximal antiviral effect. Generally, the amount of ionic zinc (i.e., Zn²⁺) in a lozenge of the invention may be in the range of about 1 mg to about 50 mg, typically in the range of about 5 mg to about 40 mg, preferably in the range of about 15 mg to about 35 mg (these ranges correspond to about 12.8 mg to about 640 mg, typically about 64 mg to about 512, preferably about 192 mg to about 448 mg zinc gluconate, insofar as ionic zinc represents approximately 12.8 wt.% of zinc gluconate).

For the treatment of colds, combinations of ionizable zinc compounds with other cold remedies, e.g., vitamin C, herbal remedies, decongestants, etc., are particularly desirable.

In treatment of halitosis, the composition does not require an added beneficial agent, insofar as the flavoring agent itself reduces bad breath for extended time periods. Incorporation of an additional beneficial agent such as an ionizable zinc compound, however, can also serve to combat halitosis. While the flavoring agent masks the odor associated with halitosis, a zinc compound as discussed above, such as zinc acetate or zinc gluconate, acts in a different manner, by combining with the volatile sulfur compounds that produce halitosis. Other agents for reducing or eliminating halitosis can also be incorporated into the composition, and may or may not target a particular cause of the problem (e.g., infections of the mouth, nasal or sinus conditions, gastrointestinal disorders, diabetes, etc.). For example, anti-infective agents such as triclosan or phenol may be suitable. In contrast to breath mints and other breath fresheners known in the art, the present composition, containing a flavoring agent and optionally one or more additional beneficial agents for treating halitosis, can reduce bad breath for up to several hours or more. With non-sugar sweeteners, lozenges, gums, etc. of the invention do not promote dental caries but nevertheless retaining a pleasant, sweet taste for an extended time period.

In a related embodiment, the tooth-whitening composition may contain a local anesthetic agent to reduce sore throat pain, and/or a local anti-infective agent to eliminate any bacteria or virii associated with the sore throat. Local anesthetics include, for example, menthol, benzocaine, bupivacaine, butambenpicrate, chlorprocaine, cocaine, dibucaine, dimethisoquin, dyclonine, etidocaine, hexylcaine, hexylresorcinol, ketarine, lidocaine, mepivacaine, phenol, phenolate, pramoxine, procaine, ropavacaine, tetracaine, tripelennamine, xylocaine, and pharmaceutically acceptable salts thereof (e.g., dimethisoquin hydrochloride, pramoxine hydrochloride) while representative anti-infective agents include amylmetacresol, benzalkonium, cetylpyridinium, chlorhexidine, dequilinium, domiphen, dichlorobenzyl alcohol, phenol, and tyrothicin. Of course, a source of zinc ion such as zinc acetate or zinc gluconate can also be incorporated into a lozenge or gum for reducing sore throat pain, insofar as such compounds exhibit antiviral activity as noted above. It will be appreciated that such compositions are also useful in treating and/or reducing pain associated with local viruses of the mouth, which are often manifested as sores or lesions (e.g., those associated with herpes infection), or with various disorders of the tongue.

The compositions of the invention are also useful in treating oral sores, including cold sores and oral mucositis. Use of anti-inflammatory agents and antibiotics to treat or prevent cold sores and oral mucositis has, in the past, proven difficult because ointments and mouth washes result in limited contact of the agent with the affected tissue. By contrast, the compositions of the invention can provide extended contact of the beneficial agent (e.g., dexamethasone) with the affected tissue, and thereby reduce the length of time required for a sore to heal. In the treatment of oral sores, a local anesthetic agent as those enumerated above may also be advantageously incorporated into a composition of the invention.

The present compositions can additionally-exhibit utility in facilitating weight reduction, insofar as the sustained release of flavor mimics the taste of food in the mouth, particular when the flavoring agent is a food flavor, e.g., a citrus oil or the like. Incorporation of a diet aid, however, will increase the utility of the composition in this regard. Diet aids include any agents that assist an individual to reduce the intake of food, regardless of mechanism. Therefore, diet aids for use herein may suppress appetite, give the feeling of "fullness," and/or increase metabolism. While any diet aid may be administered to an individual using the present compositions, exemplary diet aids include 5-hydroxytryptophan, tyrosine, phenylalanine, pseudoephedrine, ephedrine, phenylpropanolamine, chromium picolinate, aspirin, benzocaine, carnitine, and caffeine. Certain herbal preparations, mixtures, and extracts are also suitable diet aids, and include, without limitation, guarana and ma huang.

In another embodiment, the beneficial agent is one that promotes healthy teeth and gums. For instance, a fluoride-releasing lozenge may be prepared by incorporating a source of fluoride ion as a beneficial agent. Fluoride-releasing agents are well known and include sodium monofluorophosphate, sodium fluoride, and stannous fluoride. Fluoride-containing lozenges preferably contain xylitol as a sweetener, as xylitol may potentiate the action of the fluoride. Also, a local anesthetic agent, as described above, can provide for desensitization within the mouth, to alleviate a toothache, pain associated with a condition or disorder of the gums, or the pain or discomfort that may follow a dental procedure.

Another beneficial agent is nicotine, which may be in the form of the free base or an acid addition salt thereof. As an aid to smoking cessation, nicotine has been incorporated into gums and other drug delivery systems in the form of the acid addition salt, in large part to offset the bitter and unpleasant taste of the free base. Because the flavored matrix of the present compositions provides for very effective taste-masking with respect to a wide variety of beneficial agents, however, nicotine can be incorporated and released as the free base. Since the base is more readily delivered across the mucosal membrane than the salt form of the drug, the invention enables delivery of a lower dose of nicotine, particularly with lozenges. Preferred lozenges contain 2 mg, 4 mg, or 10 mg nicotine. That is, a lozenge of the invention can contain less than about 5 mg of nicotine, typically 0.1 to 2 mg, preferably 0.25 to 1.5 mg, while nevertheless providing the desired therapeutic effect. With nicotine-containing lozenges, it may be desirable to incorporate or disperse the nicotine in an excipient that reduces the volatility of the drug (e.g., mannitol, microcrystalline cellulose, colloidal silica), unless the nicotine is in the form of an acid addition salt. Also, a sweetener is virtually essential to provide taste-masking. While any of the above-mentioned sweeteners may be used, a particularly preferred sweetener in nicotine lozenges is sucralose.

While the above discussion sometimes refers to the sustained release systems of the invention as "lozenges," it is to be emphasized that the term encompasses both chewing gums and lozenge-type systems having some degree of adhesion. Such dosage forms are generally substantially flat and adhere to the gum or teeth to deliver a beneficial agent, e.g., an anti- infective agent including any of the local anti-infective agents set forth above, a local anesthetic agent, including those exemplified previously, or an anti-inflammatory agent. Anti- inflammatory agents include NSAIDS (nonsteroidal anti-inflammatory agents) such as ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, alminoprofen, butibufen, fenbufen and tiaprofenic acid; acetylsalicylic acid, apazone, diclofenac, difenpiramide, diflunisal, etodolac, flufenamic acid, indomethacin, ketorolac, meclofenamate, mefenamic acid, nabumetone, phenylbutazone, piroxicam, sulindac, and tolmetin, and corticosteroids such as hydrocortisone, hydrocortisone- 21-monoesters (e.g., hydrocortisone-21 -acetate, hydrocortisone-21-butyrate, hydrocortisone-21 - propionate, hydrocortisone-21 -valerate, etc.), hydrocortisone- 17,21-diesters (e.g., hydrocortisone- 17,21 -diacetate, hydrocortisone- 17-acetate-21 -butyrate, hydrocortisone- 17,21 - dibutyrate, etc.), alclometasone, dexamethasone, flumethasone, prednisolone, methylprednisolone, clobetasol, betamethasone fluocinonide, mometasone, triamcinolone acetonide, and the like.

Any of the beneficial agents may be in the form of a salt, ester, amide, prodrug, active metabolite, isomer, analog, or the like, provided that the salt, ester, amide, prodrug, active metabolite, isomer, or analog is pharmaceutically acceptable and retains at least some degree of the desired activity. Salts, esters, amides, prodrugs, metabolites, analogs, and other derivatives of the beneficial agents herein may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Edition (New York: Wiley- Interscience, 1992).

For example, acid addition salts are prepared from a beneficial agent in the form of a free base using conventional methodology involving reaction of the free base with an acid. Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulforύc acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. An acid addition salt may be reconverted to the free base by treatment with a suitable base. Conversely, preparation of basic salts of acid moieties that may be present on an active agent may be carried out in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like. Preparation of esters involves transformation of a carboxylic acid group via a conventional esterification reaction involving nucleophilic attack of an RO^" moiety at the carbonyl carbon. Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures. Amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine. Prodrugs and active metabolites may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system. Other derivatives and analogs of the beneficial agents may be prepared using standard techniques known to those skilled in the art of synthetic organic chemistry, or may be deduced by reference to the pertinent literature. In addition, chiral active agents may be in isomerically pure form, or they may be administered as a racemic mixture of isomers.

Methods of Manufacture:

The compositions, e.g., lozenges, of the invention are prepared by admixture of all solid components of the formulation in particulate form, followed by addition of the essential oil component, which is generally although not necessarily the only liquid in the formulation. Mixture of the solid components can be carried out using any commercially available mixing device adapted to mix powders.

The formulation process can generally be carried out at room temperature and ambient humidity, unless a particular beneficial agent or other component of the composition requires a protected environment, a lower temperature, or lower humidity. Using the appropriate weight ratio of the hydrophilic polymer to the flavoring agent as discussed supra, admixture of the components results in a pliable wet matrix that can be formed into a roll or sheet. After allowing the composition to set, typically over a 24-hour period, lozenges, gum strips, or the like are then created by cutting of the roll or die cutting of the sheet. In a preferred embodiment, the mixture of the components is compressed to form lozenges. For example, the mixture can be compressed in a two-part lozenge-shaped mold, wherein after the mixture is added to a recess within the lower half of the mold, the upper half is aligned therewith and pressure is applied to compress the mixture. Compressed lozenges can be made so as to remain intact within the mouth for extended time periods, on the order of five hours or more. It will be appreciated, however, that the present process can be tailored to provide compressed lozenges that degrade more quickly, for example by varying the proportion of flavoring agent(s) and/or excipients.

If a somewhat tacky lozenge is desired, e.g., a dosage form that adheres to the buccal mucosa for delivery of a beneficial agent, the same procedures are followed except that a lower molecular weight hydrophilic polymer is used to impart adhesive strength to the lozenge by virtue of the tacky surface provided. Alternatively, or in addition, one or more adhesive polymers can be incorporated into the lozenge formulation to provide the desired degree of adhesion, as described elsewhere herein.

Chewing gums may be prepared by first formulating the wet matrix as described above, i.e., by admixing the hydrophilic polymer and the flavoring agent. Then, the matrix, the tooth-whitening oxidizing agent, along with any additional components, e.g., sweeteners, colorants, or other additives, is admixed with a selected chewing gum base as described earlier herein. Mixing may be effected using any suitable mixing device, e.g., a ribbon blender. The resultant chewing gum is then manufactured into strips or tablets of a desired size.

The lozenges or gums so prepared are individually packaged in a manner that promotes shelf life and maximizes the stability of the flavoring agent. These requirements translate into a package design in which both the air space and exposed surface area of the lozenge are minimized, and in which the packaging material used has very low permeability to vapor. A plastic-lined foil, wherein the plastic is a low permeability material, is optimal. Ideally, the packaging material should be in contact with at least 85% of the surface of the lozenge to minimize loss of flavor, and packaging materials that do not transmit organic vapors are optimal. For example, polyolefinic materials such as poly(vinylidene chloride), polyethylene (including low density and higher density polyethylenes), polypropylene, and copolymers thereof represent suitable packaging materials.

As alluded to earlier herein, the lozenges and other compositional units of the invention may be prepared in any number of shapes and sizes, and the invention is not limited in this regard. Different shapes and sizes may be desirable for different applications. Typical dimensions, however, are on the order of 0.4" x 0.5" x 0.2" for lozenges, while lozenge weight is generally in the range of about 0.4 to 0.8 g. For chewing gums, the dimensions will generally be somewhat different, insofar as flat, elongated strips and/or larger tablets are often preferred.

It is to be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the description above as well as the examples that follow are intended to illustrate and not limit the scope of the invention. Other aspects, advantages and modifications within the scope of the invention will be apparent to those skilled in the art to which the invention pertains.

All patents, patent applications, journal articles, and other references cited herein are incorporated by reference in their entireties.

Example 1 - Preparation of Flavored Tooth- Whitening Lozenges Lozenges were prepared with the following composition: Essential oils (peppermint and spearmint, combined): 25 wt.% ETHOCEL^® 100 FP (obtained from The Dow Chemical Company, Midland, MI), 22% Carbamide peroxide, 12% Gum arabic, 9% Xanthan gum, 9% Menthol, 9% Sucralose, 6% Xylitol, 6% Zinc gluconate, 1.6%.

AU components except the essential oils were combined at room temperature and ambient humidity. The essential oils were then added and mixing continued. Admixture of the components resulted in a soft, wet composition that was allowed to set for 24 hours in the form of a sheet, and lozenges were then cut therefrom. The lozenges were soft, pliable, and nontacky, and provided sustained release of the tooth-whitening agent and peppermint flavor for approximately 4 hours.

Example 2 - Whitening Evaluations

A pilot study with eight subjects was conducted with the lozenges of Example 1. Each subject used 24 lozenges, taking two per day. FIG. 1 shows the results of the study in terms of shades of whitening over time. On the basis of that study, performance was projected out to 48 lozenges (24 days of use), with the results depicted in FIG. 2. A comparison was made to published data regarding the commercial product Crest Whitestrips Supreme. (Swift, E., et al. Three- Week Clinical Trial of a 14% Hydrogen-Peroxide, Strip-based Bleaching System, Compendium, August 2004, Vol. 25, No. 8 (Supp. 2).) The average 7.8 shades of improvement achieved by the lozenges of the invention in 12 days with 24 lozenges compares with 7.5 shades improvement in 21 days with 84 strips achieved by Crest Whitestrips Supreme.

Example 3 - Stability Evaluations

Lozenges were prepared according to Example 1 and stored for a period of five months. Upon visual inspection there was no swelling, blistering, or change in color or shape. This is believed to indicate that the carbamide peroxide has not significantly reacted with any of the excipients, since such a reaction would tend to produce swelling or blistering. Lozenges prepared according to Example 1 and stored for a period of about four months were used in clinical testing and found to produce the expected magnitude of tooth whitening effect.

Claims

CLAIMSWe claim:

1. A flavored, sustained release tooth-whitening composition comprising a soft solid matrix unit that provides for sustained release of a tooth-whitening oxidizing agent in the oral cavity throughout a time period of at least 15 minutes.

2. A flavored, sustained release tooth-whitening composition comprising a son solid matrix unit that provides for sustained release of a tooth-whitening oxidizing agent in the oral cavity, wherein, following use of at least 24 of said lozenges by an individual throughout a time period of less than one month, tooth whitening of at least one shade is achieved.

3. A flavored, sustained release tooth-whitening composition comprising a soft solid matrix unit that provides for sustained release of a tooth- whitening oxidizing agent in the oral cavity, wherein, following use of at least 36 of said lozenges by an individual throughout a time period of less than six weeks, tooth whitening of at least two shades is achieved.

4. A flavored, sustained release tooth-whitening composition comprising a soft solid matrix unit that provides for sustained release of a tooth-whitening oxidizing agent in the oral cavity, wherein, following use of at least 48 of said lozenges by an individual throughout a time period of less than two months, tooth whitening of at least three shades is achieved.

5. A flavored, sustained release tooth-whitening composition comprising a soft solid matrix unit of a water-insoluble hydrophilic polymer, an essential oil component that plasticizes the hydrophilic polymer, and up to 20 wt. % of a tooth-whitening oxidizing agent, wherein, in an aqueous environment, the composition gradually releases the oxidizing agent and the flavoring agent throughout a time period of at least 15 minutes.

6. The tooth-whitening composition of claim 5, wherein the weight ratio of the hydrophilic polymer to the essential oil component is selected to provide sustained release of the oxidizing agent and the flavoring agent throughout a time period in the range of about 15 minutes to about 4 hours.

7. The tooth-whitening composition of claim 5, wherein the weight ratio of the hydrophilic polymer to the essential oil component is selected to provide sustained release of the oxidizing agent and the flavoring agent throughout a time period in the range of about 15 minutes to about 2 hours.

8. The tooth-whitening composition of claim 5, wherein the weight ratio of the hydrophilic polymer to the essential oil component is selected to provide sustained release of the oxidizing agent and the flavoring agent throughout a time period of about 15 minutes to about 60 minutes.

9. The tooth-whitening composition of claim 5, wherein the weight ratio of the hydrophilic polymer to the flavoring agent is selected to provide sustained release of the flavoring agent throughout a time period of at least 60 minutes.

10. The tooth-whitening composition of claim 9, wherein the weight ratio of the hydrophilic polymer to the flavoring agent is selected to provide sustained release of the flavoring agent throughout 1:1 time period of at least 2 hours.

11. The tooth-whitening composition of claim 5, wherein the hydrophilic polymer has a particle size in the range of about 10 microns to about 90 microns.

12. The tooth-whitening composition of claim 11, wherein the hydrophilic polymer has a particle size in the range of about 30 microns to about 60 microns.

13. The tooth-whitening composition of any one of claims 5, 11, and 12 wherein the hydrophilic polymer is ethyl cellulose.

14. The tooth-whitening composition of claim 13, wherein the ethyl cellulose has a solution viscosity in the range of about 5 cP to about 150 cP as determined at 25°C using a 5 wt. % aqueous solution.

15. The tooth-whitening composition of claim 14, wherein the ethyl cellulose has a solution viscosity ill the range of about 50 cP to about 125 cP as determined at 25°C using a 5 wt. % aqueous solution.

16. The tooth-whitening composition of claim 15, wherein the ethyl cellulose has a solution viscosity in the range of about 90 cP to about 110 cP as determined at 25°C using a 5 wt. % aqueous solution.

17. The tooth-whitening composition of claim 5, wherein the essential oil component comprises an essential oil.

18. The tooth-whitening composition of claim 17, wherein the essential oil imparts a food flavor.

19. The tooth-whitening composition of claim 18, wherein the essential oil is a citrus oil.

20. The tooth-whitening composition of claim 18, wherein the essential oil is a mint oil.

21. The tooth-whitening composition of claim 20, wherein the mint oil is peppermint oil, spearmint oil, or a combination thereof.

22. The tooth-whitening composition of claim 5, wherein the essential oil component comprises a constituent of an essential oil.

23. The tooth-whitening composition of claim wherein the essential oil component is selected from terpenes, sesquiterpenes, and combinations thereof

24. The tooth-whitening composition of claim 1, wherein the weight ratio of the hydrophilic polymer to the essential oil component is in the range of approximately 1:5 to 2: 1.

25. The tooth- whitening composition of claim 24, wherein the weight ratio is in the range of approximately 1:2 to 1.5:1.

26. The tooth-whitening composition of claim wherein the weight ratio is in the range of approximately 1:1.5 to 1.5:1.

27. The tooth-whitening composition of claim 5, wherein the tooth-whitening oxidizing agent is selected from peroxides, chlorites, perborates, percarbonatcs, persulfates, peroxyacids, and combinations thereof.

28. The tooth- whitening composition of claim wherein the tooth-whitening oxidizing agent comprises a peroxide.

29. The tooth-whitening composition of claim 28, wherein the peroxide is selected from hydrogen peroxide, carbamide peroxide, and combinations thereof.

30. The tooth-whitening composition of claim 29, wherein the peroxide comprises carbamide peroxide.

31. The tooth-whitening composition of claim 5, wherein the tooth-whitening oxidizing agent represents about 5 wt. % to about 20 wt. % of the composition.

32. The tooth-whitening composition of claim 31, wherein the tooth-whitening oxidizing agent represents about 7.5 wt. % to about 17.5 wt. % of the composition.

33. The tooth- whitening composition of claim wherein the tooth- whitening oxidizing agent represents about 10 wt. % to about 15 wt. % of the composition.

34. The tooth-whitening composition of claim 33, wherein the tooth-whitening oxidizing agent represents about 12 wt. % of the composition,

35. The tooth-whitening composition of claim 5, further including an effective sweetening amount of a sweetener selected from a sugar, a non-sugar sweetening agent, or a mixture thereof.

36. The tooth-whitening composition of claim 35, wherein the sweetener is a sugar.

37. The tooth- whitening composition of 35, wherein the sweetener is a non-sugar sweetening agent.

38. The tooth- whitening composition of claim 37, wherein the non-sugar sweetening agent is selected from aspartame, saccharin, sodium saccharin, calcium saccharin, sucralose, acesulfame-K, sorbitol, xylitol, steviosin, steviol, mannitol, erythritol, lactitol, and mixtures thereof

39. The tooth-whitening composition of claim 5, further including an amount of a gum base effective to render the composition chewable, as a chewing gum.

40. The tooth-whitening composition of claim 5, further comprising an effective amount of a beneficial agent in addition to the tooth-whitening agent.

41. The tooth- whitening composition of claim 40, wherein the beneficial agent is a source OfZn²⁺.

42. The tooth-whitening composition of claim 41, wherein the beneficial agent is selected from the group consisting of zinc gluconate, acetate, chloride, propionate, butyrate, n- butyrate, β-hydroxybutyrate, benzoate, formate, and sulfate.

43. The tooth-whitening composition of claim 40, wherein the beneficial agent is selected from zinc gluconate and zinc acetate.

44. The tooth-whitening composition of claim 41, further comprising at least one additional agent for treating the common cold.

45. The tooth- whitening composition of claim 44, wherein the at least one additional agent is vitamin C.

46. The tooth- whitening composition of claim 40, wherein the beneficial agent is a local anesthetic agent.

47. The tooth-whitening composition of claim 40, wherein the beneficial agent is a local antibiotic.

48. The tooth-whitening composition of claim 40, wherein the beneficial agent is a diet aid.

49. The tooth-whitening composition of claim 40, wherein the beneficial agent is a source of fluoride ion.

50. The tooth-whitening composition of claim 40, wherein the beneficial agent is nicotine.

51. The tooth-whitening composition of claim 40, wherein the beneficial agent is a tooth re-mineralization agent.

52. The tooth- whitening composition of claim 40, wherein the beneficial agent is a tooth desensitizing agent.

53. The tooth-whitening composition of claim 5, further comprising a colorant.

54. The tooth-whitening composition of claim 5, further comprising at least one additive selected from release rate accelerants, release rate retardants, adhesion-increasing agents, adhesion-reducing agents, flavor stabilizers, flavor diluents, pH-adjusting agents, preservatives, lubricants, and fillers.

55. The tooth-whitening composition of claim 5, comprising a lozenge.

56. The tooth-whitening composition of claim wherein the lozenge is mounted on a support that can be held and manipulated from a location external to the oral cavity.

57. The tooth-whitening composition of claim wherein the support is a lollipop support.

58. The tooth-whitening composition of claim 5, comprising a chewing gum.

59. A method for achieving sustained release of a tooth- whitening oxidizing agent in the mouth throughout a time period of at least 15 minutes, comprising administering the composition of claim 1 to the mouth of an individual.

60. The method of claim 59, wherein the individual manipulates the lozenge within the mouth during use to maximize contact of the lozenge with the front surfaces of the teeth.

61. A method of manufacturing a flavored tooth-whitening composition comprising a soft solid matrix unit, comprising the steps of mixing at least one tooth-whitening active and excipients, adding an essential oil or mixture of essential oils while continuing to mix, rolling the mix, and separating the rolled mix into individual dosage units.

62. A flavored, sustained release tooth-whitening composition comprising a soft solid matrix unit that has a shelf stability of at least six months.