WO2013162404A1

WO2013162404A1 - Hydrophilic pressure sensitive bioadhesives with targeted adhesion towards teeth and tooth care compositions based thereon

Info

Publication number: WO2013162404A1
Application number: PCT/RU2012/000377
Authority: WO
Inventors: Mikhail Majorovich FELDSTEIN; Galina Grigorevna PEREPELITSA; Aleksej Removich KHOKHLOV
Original assignee: Feldstein Mikhail Majorovich; Perepelitsa Galina Grigorevna; Khokhlov Aleksej Removich
Priority date: 2012-04-27
Filing date: 2012-05-14
Publication date: 2013-10-31
Also published as: EP2841045A4; EP2841045A1; RU2517142C2; RU2012116982A

Abstract

Present invention relates to adhesive hydrogel compositions, namely to "smart" water-absorbing pressure-sensitive bioadhesive films, which possess strong targeted adhesion towards teeth but do not adhere to other mucosal tissues in oral cavity. The compositions comprise a film-forming, hydrophilic polymer and other hydrophilic polymeric, oligomeric or low-molecular weight components, providing a complex formation with particular values of glass transition temperature, elasticity modulus G\ loss tangent, swelling degree and swell ratio. The film-forming, hydrophilic polymer is present in a higher concentration than others composition components, and the latter contain complementary reactive functional groups which are capable of forming noncovalent hydrogen, electrostatic or ionic bonds with the functional groups of the hydrophilic film-forming polymer. In swollen state the "smart" hydrophilic pressure- sensitive bioadhesive is softer than the dental substrate but harder than the mucosal tissues in oral cavity. The compositions find utility as tooth whitening strips or gels, and with this purpose contain a whitening agent, preferably peroxide.

Description

HYDROPHILIC PRESSURE SENSITIVE BIOADHESIVES WITH

TARGETED ADHESION TOWARDS TEETH AND TOOTH CARE COMPOSITIONS BASED THEREON TECHNICAL FIELD

This invention relates generally to adhesive hydrogel compositions for tooth whitening, and more particularly relates to "smart" water-absorbing pressure sensitive bioadhesive films which manifest strong adhesion towards teeth but no adhesion towards other mucosal tissues in oral cavity.

BACKGROUND ART

Discoloration of the teeth is a widespread problem, occurring in two out of three adults. Dental discoloration is considered an aesthetic flaw, and can be particularly distressing or troublesome in situations and professions where showing clean and white teeth is essential.

A tooth is composed of an inner dentin layer and an outer, protective layer that is composed of hard enamel but slightly porous. 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 compounds such as tannins and other polyphenols. These compounds become trapped in or bound to the proteinaceous layer on the surface of teeth, and can penetrate the enamel and even the dentin. On occasion, staining can arise from sources within the tooth, such as tetracycline, which may become deposited in the teeth if administered to an individual when young.

Surface staining can usually be removed by mechanical tooth cleaning. However, discolored enamel or dentin is not amenable to mechanical methods of tooth cleaning, and chemical methods, which can penetrate into the tooth structure, are required to remove the stains. The most effective treatments for dental discoloration are compositions containing an oxidizing agent, such as hydrogen peroxide, that is capable of reacting with the chromogen molecules responsible for the discoloration, and rendering them either colorless or water-soluble, or both.

Consequently, tooth whitening compositions generally fall into two categories: (1) gels, pastes, and liquids, including toothpastes that are mechanically agitated at the stained tooth surface in order to affect tooth stain removal through abrasive erosion of surface stains; and (2) gels, pastes, or liquids that accomplish a tooth-bleaching effect by a chemical process while in contact with the stained tooth surface for a specified period, after which the formulation is removed. In some cases, an auxiliary chemical process, which may be oxidative or enzymatic, supplements the mechanical process.

Some dental compositions such as dentrifices, toothpastes, gels, and powders contain active oxygen or hydrogen peroxide liberating bleaching agents. Such bleaching agents include peroxides, percarbonates, and perborates of the alkali and alkaline earth metals or complex compounds containing hydrogen peroxide. Also, peroxide salts of the alkali or alkaline earth metals are known to be useful in whitening teeth.

Of the many peroxides available to the formulator of tooth whitening compositions, hydrogen peroxide (and its adducts or association complexes, such as carbamide peroxide and sodium percarbonate) has been used almost exclusively. The chemistry of hydrogen peroxide is well known, although the specific nature of its interactions with tooth chromogens is poorly understood. It is believed that hydrogen peroxide destroys tooth chromogens by oxidizing unsaturated carbon-carbon, carbon- oxygen, and carbon-nitrogen bonds found in the stain molecules, thus rendering them colorless or soluble.

A related class of compound, the peroxyacids, has been used in laundry detergents to effectively whiten clothes, due primarily to their stability in solution and their specific binding abilities to certain types of stain molecules. A number of stable, solid peroxyacids have been used, including diperoxydodecanoic acid and the magnesium salt of monoperoxyphthalic acid. Other peroxyacids, such as peroxyacetic acid, are available as solutions containing an equilibrium distribution of acetic acid, hydrogen peroxide, peroxyacetic acid, and water. Alternatively, a peroxide donor such as sodium perborate or sodium percarbonate is formulated together with a peroxyacid precursor. Upon contact with water, the peroxide donor releases hydrogen peroxide which then reacts with the peroxyacid precursor to form the actual peroxyacid. Examples of peroxyacids created in situ include peroxyacetic acid (from hydrogen peroxide and tetraacetylethylenediamine) and peroxynonanoic acid (from hydrogen peroxide and nonanoyloxybenzene sulfonate).

Peroxyacids have also been used in oral care compositions to whiten stained teeth. U.S. Patent No. 5,279,816 describes a method of whitening teeth comprising the application of a peroxyacetic acid-containing composition having an acid pH. EP 545,594 Al describes the use of peroxyacetic acid in preparing a composition for whitening teeth. The peroxyacetic acid may be present in the composition, or alternatively, may be generated in situ by combining a peroxide source with a peroxyacetic acid precursor during use. For example, U.S. Patent N°. 5,302,375 describes a composition that generates peroxyacetic acid within a vehicle in situ by combining water, acetylsalicylic acid and a water-soluble alkali metal percarbonate.

The most commonly used dental whitening agent is carbamide peroxide. Carbamide peroxide had been used by dental clinicians for several decades as an oral antiseptic, and tooth bleaching was an observed side effect of extended contact time. Over-the-counter compositions of 10% carbamide peroxide are available as GLY- OXIDE® by Marion Laboratories and PROXIGEL® by Reed and Carnrick, which are low-viscosity compositions that must be held in a tray or similar container in order to provide contact with the teeth. A bleaching gel which is able to hold a comfortable-fitting dental tray in position for an extended time period is available under the trademark OPALESCENCE® from Ultradent Products, Inc. in South Jordan, Utah.

In order for such compositions to stay in place, the compositions must be a viscous liquid or a gel. The use of dental trays also requires that the tray be adapted for comfort and fit so that the tray will not exert pressure or cause irritation to the person's teeth or gums. Such whitening compositions necessarily should be formulated so as to be sufficiently sticky and viscous to resist dilution by saliva.

In one method of whitening an individual's teeth, a dental professional will construct a custom made dental bleaching tray for the patient from an impression made of the patient's dentition and prescribe the use of an oxidizing gel to be dispensed into the bleaching tray and worn intermittently for a period of from about 2 weeks to about 6 months, depending upon the severity of tooth staining. These oxidizing compositions, usually packaged in small plastic syringes or tubes, are dispensed directly by the patient into the custom-made tooth-bleaching tray, held in place in the mouth for contact times of greater than about 60 minutes, and sometimes as long as 8 to 12 hours. The slow rate of bleaching is in large part the consequence of the very nature of formulations that are developed to maintain stability of the oxidizing composition.

For example, U.S. Patent No. 6,368,576 to Jensen describes tooth whitening compositions that are preferably used with a tray so that the composition is held in position adjacent to the person's tooth surfaces to be treated. These compositions are described as a sticky matrix material formed by combining a sufficient quantity of a tackifying agent, such as carboxypolymethylene, with a solvent, such as glycerin, polyethylene glycol, or water.

In another example, U.S. Patent No. 5,718,886 to Pellico describes a tooth whitening composition in the form of a gel composition containing carbamide peroxide dispersed in an anhydrous gelatinous carrier, which includes a polyol, a thickener, and xanthan gum.

Yet another example is described in U.S. Patent No. 6,419,905 to Hernandez, which describes the use of compositions containing carbamide peroxide (0.3-60%), xylitol (0.5-50%), a potassium salt (0.001 -10%) and a fluorine salt (0.15-3%), formulated into a gel that contains between 0.5 and 6% by weight of an appropriate gelling agent.

A tooth whitening composition that adheres to the teeth is described in U.S. Patent Nos. 5,989,569 and 6,045,81 1 to Dirksing. According to these patents, the gel contains 30-85% glycerin or polyethylene glycol, 10-22% urea/hydrogen peroxide complex, 0- 12% carboxypolymethylene, 0-1% sodium hydroxide, 0-100% triethanolamine (TEA), 0- 40% water, 0-1% flavor, 0-15% sodium citrate, and 0-5% ethylenediaminetetraacetic acid. The preferred gel according to Dirksing has a viscosity between 200 and 1 ,000,000 cps at low shear rates (less than one s^"1), and is sufficiently adhesive so as to obviate the need for a tray.

Currently available tooth-bleaching compositions have a significant disadvantage in that they cause tooth sensitization in over 50% of patients. Tooth sensitivity may result from the movement of fluid through the dentinal tubules, which is sensed by nerve endings in the tooth, due to the presence of glycerin, propylene glycol, and polyethylene glycol in these compositions. This can result in varying amounts of tooth sensitivity following exposure of the teeth to heat, cold, overly sweet substances, and other causative agents.

Prolonged exposure of teeth to bleaching compositions, as practiced at present, has a number of adverse effects in addition to that of tooth sensitivity. These adverse effects include leaching of calcium from the enamel layer at a pH less than 5.5; penetration of the intact enamel and dentin by the bleaching agents and risking damage to pulpal tissue; and dilution of the bleaching compositions with saliva resulting in leaching from the dental tray and subsequent ingestion by the user.

Some oxidizing compositions (generally having relatively high concentrations of oxidizers) are applied directly to the tooth surface of a patient in a dental office setting under the supervision of a dentist or dental hygienist. Theoretically, such tooth whitening strategies yield faster results and better overall patient satisfaction. However, due to the high concentration of oxidizing agents contained in these so called "in-office" compositions, they can be hazardous to the patient and practitioner alike if not handled with care. The patient's soft tissues (the gingiva, lips, and other mucosal surfaces) must first be isolated from potential exposure to the active oxidizing agent by the use of a perforated rubber sheet (known as a rubber dam), so that only the teeth protrude. Alternatively, the soft tissue may be isolated from the oxidizers to be used in the whitening process by covering the soft tissue with a polymerizable composition that is shaped to conform to the gingival contours and subsequently cured by exposure to a high intensity light source. Once the soft tissue has been isolated and protected, the practitioner may apply the oxidizing agent directly onto the stained tooth surfaces for a specified period of time or until a sufficient change in tooth color has occurred. Typical results obtained through the use of an in-office tooth whitener, range from about 2 to 3 shades (as measured with the VITA Shade Guide, VITA Zahnfarbik).

The range of tooth shades in the VITA Shade Guide varies from very light (Bl) to very dark (C4). A total of 16 tooth shades constitute the entire range of colors between these two endpoints on a scale of brightness. Patient satisfaction with a tooth whitening procedure increases with the number of tooth shade changes achieved, with a generally accepted minimum change desirable of about 4 to 5 VITA shades.

It is very desirable, with respect to dental care products for tooth whitening, to provide dental care products utilizing an adhesive hydrogel that includes a whitening agent for removing stains from an individual's teeth. Compositions that do not require the use of dental trays to provide contact between the bleaching agent and the teeth are particularly desirable. Such products ideally cause minimal or no tooth sensitivity, minimize or eliminate leakage of the whitening agent resulting in ingestion by the user or resulting in damage or irritation to the gums or mucous membranes of the mouth, provide for longer wear duration, sustained dissolution of the tooth whitening agent, improved efficacy, and are well tolerated by users. It is also desirable to provide a tooth whitening dental care product that is a solid composition and self-adhesive film but that does not stick to the fingers of the user, or that is a non-solid (e.g., liquid or gel) and forms a film when dry.

Such tooth whitening hydrogel and bioadhesive film compositions that adhere to the teeth for a prolonged period of time and release whitening agent gradually with controlled rate are described in U.S. Patent Applications Nos. 2003/0152528, 2003/0235549, 2004/0105834 and 2006/0171906 by P. Singh, G.W. Cleary, M.M. Feldstein, D.F. Bairamov at al. According to these Patent Applications, the compositions are provided, wherein the formulation comprises a water-swellable, water-insoluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen or electrostatic bonding to the hydrophilic polymer, and a whitening agent, preferably a peroxide. The compositions find utility as tooth whitening hydrogel or strip formulations and are applied to the teeth in need of whitening, and then removed when the degree of whitening has been achieved. In certain embodiments, the tooth whitening composition is translucent, comprises a mixture of tooth whitening agents, with a first whitening agent selected so as to release peroxide gradually upon contact with moisture and produce an alkaline pH, and a second whitening agent selected so as to release peroxide rapidly upon contact with moisture. The new tooth whitening composition provides sustained release of high levels of whitening agent and is moisture-activated without significant swelling. A preferred system for applying the composition to the teeth is flexible, self-adhesive, and well-tolerated by users. Methods for preparing and using the compositions are also disclosed.

A most commercially successful of these compositions is that underlying the Crest 3D White Whitestrips^® Advanced Seal, available from Procter & Gamble Company (see U.S. Patent Application No 2006/0171906 and PCT Application No WO 2006/069236 to P. Singh, E.S. Lee, A. Sagi, M.M. Feldstein, D.F. Bairamov). New Crest Whitestrips^® Advanced Seal utilizes the Corplex™ technology that combines the principles of dermal pressure sensitive adhesives (PSAs) and bioadhesives (BAs) to create the perfect adhesive balance and hold the strip in place. The fundamentals of this technology were first described in G.W. Cleary, M.M. Feldstein, E. Beskar, CORPLEX™ - A Versatile Drug Delivery Platform for Dry and Wet Dermal and Mucosal Surfaces, Pharmatech, Business Briefing, 2003, p 1 - 4; and later improved and extended into the molecular design technology of novel PSAs with tailored performance properties, disclosed in M.M. Feldstein, G.W. Cleary, P. Singh, Hydrophilic Adhesives, in: I. Benedek, M.M. Feldstein (Editors), Technology of Pressure-Sensitive Adhesives and Products (Handbook of Pressure-Sensitive Adhesives and Products), CRC - Taylor & Francis, Boca Raton, London, New York, 2009, Chapter 7, pp. 7-1 - 7-80; and in D.F. Bayramov, P. Singh, G.W. Cleary, R.A. Siegel, A.E. Chalykh, M.M. Feldstein, Non-covalently crosslinked hydrogels displaying a unique combination of water -absorbing, elastic and adhesive properties, Polym. Int. 2008, vol. 57, 785-790.

In dry state, the composition shows no or negligible adhesion to dry substrates. However, as the composition absorbs over 12 wt. % of moisture or is exposed to wet substrates, the adhesion increases achieving high steady-state level in the range from 10 to 20 J/m² (see P.E. Kireeva, M.B. Novikov, P. Singh, G.W. Cleary, M.M. Feldstein, Tensile properties and adhesion of water absorbing hydrogels based on triple poly(N- vinyl pyrrolidone) I poly(ethylene glycol) I poly (methacry lie acid - co - ethylacrylate) blends, J. Adhesion Sci. Technol. 2007, vol. 21 JTs. 7, p. 531 - 557).

Activated by naturally moisture in the mouth, such as saliva, the Corplex™ adhesive platform in Advanced Seal tooth whitening strip provides instant adhesion and instantly molds to teeth with no slipping in the course of moisture absorbtion and swelling. After use, the PSA film is easily removed from teeth with no mess and no residue.

With this purpose, a representative tooth whitening system of the prior-art invention is composed of an interior tooth whitening layer bisected by a nonwoven layer, such that the interior tooth whitening layer includes an upper region and a lower region. The upper region is laminated to the outer backing layer, composed of a relatively hydrophobic, permeable polymer and containing 1.0 wt. % to 30.0 wt. % tooth whitening agent. The outer backing layer provides the exterior surface of the system following application to the teeth. Removable release liner covers the otherwise exposed surface of the lower region of the interior tooth whitening layer prior to use. The suitable nonwoven mesh bisecting the interior whitening agent layer into two separate layers is normally polyamide, obtained from Spunfab.

The function of the outer backing member is to protect the multilayer tooth whitening system from adherence to mucous tissues of the tongue, gingiva and palate, and thus keep the strip on teeth. The function of nonwoven mesh in adhesive layer is to prevent slipping the strip.

Thus, the Advanced Seal tooth whitening strip is four-layer device. The special outer layer holds the strip securely on teeth. The whitening layer delivers the same high- performance whitening ingredient used by professional dentists. The inner mesh layer keeps the whitening ingredient firmly on teeth, preventing gel from spreading to other areas of the mouth. The final release liner provides the strips with stable backing for easy application.

In a typical embodiment, the Advanced Seal tooth whitening system is provided that comprises a flexible strip, or backing layer (also referred to herein as an "outer layer"), in contact with a tooth whitening composition of the invention. The backing layer may comprise any suitable material, e.g., polymer, woven, non-woven, foil, paper, rubber, or a combination thereof, such as a laminate. The backing layer may be erodible, as described in U.S. Patent Publication No. 2004/0105834. Generally, the system will also include a removal release liner that covers the tooth whitening composition prior to use and prevents exposure of the composition to air.

In this embodiment, the system includes two flexible, soft layers with differential permeability, the outer layer being measurably permeable but somewhat less permeable than the inner layer. Tooth whitening agent is present in both layers, with the outer layer essentially serving as an additional reservoir for the whitening agent(s). The outer layer is relatively hydrophobic, such that the system is prevented from sticking to the lips and releasing any significant amount of hydrogen peroxide into the mouth in a direction away from the teeth.

In this way, the new Crest Whitestrips^® Advanced Seal is rather heavy multilayer device that includes normally two nontransparent members: the polyamide network in the interior adhesive layer and outer backing film. This multilayer structure imparts to the strip appreciable heaviness that hampers user's capacity to speak on phone during the session of whitening the teeth. In addition, availability of opaque layers makes the strip visible on teeth and creates inconvenience under its application outside home.

In this connection, it would be advantageous to provide a single-layer, high- performance, thin, flexible and transparent tooth whitening strip for longer wear duration that provides the confidence to whiten the teeth anywhere, anytime, whether the user is on-the-go, talking on the phone or drinking water, allowing him to go about his day without interruption.

It would be also desirable to provide a tooth-whitening product for every-time application, including night-time usable tooth-whitening product, which could self-erode after the active agent has been released in sustained manner or the desired therapeutic or cosmetic effect has been achieved, owing to gradual polymer film dissolution in saliva, being well tolerated by patients and improving their compliance. The instant invention addresses these needs.

SUMMARY OF THE INVENTION

It is a primary object of the invention to provide a tooth whitening composition and system that address the above-mentioned needs in the art. The new tooth whitening composition provides sustained release of high levels of whitening agent and is moisture- activated without significant swelling. The preferred system for applying the composition to the teeth, as will be discussed in detail infra, is flexible, self-adhesive to teeth but inadherent to mucosal tissues of oral cavity, invisible on teeth and generally well- tolerated by users, gradually eroding during long-term wear.

In a first embodiment, an improved tooth whitening strip is provided that is based on "smart" moisture-absorbing PSA that possesses high adhesion towards teeth but no adhesion to other wet mucosal tissues in oral cavity (tongue, gingival, palate).

In another embodiment, a tooth whitening composition comprises at least one tooth whitening agent, or incorporates a mixture of tooth whitening agents, with a first whitening agent selected so as to release peroxide gradually upon contact with moisture and produce an alkaline or acidic pH, and a second whitening agent selected so as to release peroxide rapidly upon contact with moisture.

In a further embodiment, a tooth whitening composition is provided that comprises an admixture of:

a first whitening agent that is inert in a dry environment but activated upon contact with moisture to release hydrogen peroxide;

a second whitening agent that is inert in a dry environment but activated upon contact with aqueous base or acid; and

a water-swellable, water-insoluble polymer.

In this embodiment, absorbed moisture results in degradation of the whitening agent to yield free radicals at a much faster rate. Free radicals react with stained teeth and render stains colorless. The overall result of both decreased and increased pH is faster whitening. The water-swellable, water-insoluble polymer may be, by way of example, a cellulosic polymer such as a cellulose ester, an acrylic acid and/or acrylate copolymer, or a mixture of such polymers. For instance, a mixture of acrylic acid and/or acrylate copolymers can be advantageously provided by combining an anionic copolymer with a cationic copolymer such that the copolymers ionically associate with each other, yielding a polymer matrix. An ionically bound polymer matrix reduces swelling of the composition in an aqueous environment, and also allows the tooth whitening agents to remain in the composition longer than would otherwise be possible. These compositions generally, although not necessarily, also contain a crosslinked hydrophilic polymer, e.g., a covalently crosslinked hydrophilic polymer, a blend of a hydrophilic polymer and a relatively low molecular weight complementary oligomer that is capable of crosslinking the hydrophilic polymer via hydrogen bonding, or a combination thereof.

a tooth whitening agent that is inert in a dry environment but activated in the presence of moisture; and

at least two water-swellable polymers, wherein a first water-swellable polymer is a polyacid, a second water-swellable polymer is a polybase, and the polymers are ionically or H-bonded associated with each other to form a water-swellable, water- insoluble polymer matrix.

In this embodiment, an ionically or H-bonded associated polymer matrix is provided as described above, but the composition contains a single tooth whitening agent that is moisture-activated. These compositions will also contain, in most instances, a crosslinked hydrophilic polymer as described above.

In another embodiment, a tooth whitening composition is provided that comprises: 1.5 wt.% to 30 wt.% of a hydrophilic polymer composition composed of (a) a covalently crosslinked hydrophilic polymer, and/or (b) a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding thereto; 40 wt.% to 90 wt.% of at least one water-swellable, water-insoluble polymer; and at least one tooth whitening agent.

The composition optionally comprises a low molecular weight plasticizer, and may also comprise at least one additive selected from the group consisting of fillers, preservatives, pH regulators, softeners, thickeners, colorants (e.g., pigments, dyes, refractive particles, etc.), flavorants (e.g., sweeteners, flavors), stabilizers, toughening agents and detackifiers.

In a preferred method of using the composition, the tooth whitening composition is applied to the teeth in need of whitening, and then gradually erodes or removed when the degree of whitening has been achieved. In certain embodiments, the tooth whitening composition is translucent, and the composition is removed when the user is satisfied with the degree of whitening achieved.

Yet another aspect of the invention pertains to a composition comprising a water- swellable, water-insoluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and an agent selected from the group consisting of peroxides, carbamide peroxide, metal chlorites, perborates, percarbonates, peroxyacids, and combinations thereof.

In several embodiments of this invention the bioadhesive compositions with targeted adhesion to teeth have been disclosed that contain a non-covalent complex of hydrophilic film-forming polymer with complementary polymer, oligomer or low- molecular weight compounds as a platform for tooth whitening products. Such complexes can be formed by hydrogen or ionic bonding of the complementary components.

Another aspect of the invention relates to a method for preparing a hydrogel film suitable for incorporation into a tooth whitening composition (?). This method comprises preparing a solution or a gel of a water-swellable, water-insoluble polymer, a hydrophilic polymer, and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, in a solvent; depositing a layer of the solution on a substrate to provide a coating thereon; and heating the coated substrate to a temperature in the range of about 80°C to about 100°C for a time period in the range of about 1 to about 4 hours, thereby providing a hydrogel film on the substrate.

The method further comprises loading the hydrogel film with the whitening agent, thereby providing the tooth whitening composition.

The "smart" adhesive tooth whitening compositions of the invention provide a number of significant advantages relative to the prior art. In particular, the smart bio-PSA compositions:

(1) provide ease of handling;

(2) strongly adhere towards teeth but possess no adhesion towards other mucosal tissues of tongue, gums and palate in oral cavity;

(3) require no backing film protecting the bio-PSA tooth whitening layer from re-adherence to tongue and other mucosal tissues in mouth;

(4) are readily modified during manufacture so that properties such as adhesion, absorption, translucence, erosion time and swelling can be controlled and optimized;

(5) can be formulated so that tack increases or decreases in the presence of moisture so that the composition is not sticky until moistened;

(6) minimize leakage of the whitening agent from the composition into the user's mouth;

(7) can be fabricated in translucent from, enabling the user to view the extent of whitening without removing the hydrogel composition from the teeth, or be invisible on the teeth;

(8) minimize damage to gums or mucous membranes in the mouth;

(9) can be worn comfortably and unobtrusively ;

(10) are easily removed from the teeth, and leave no residue;

(11) are amenable to extended duration of wear; and sustained and controlled release of the whitening agent;

(12) can be applied to teeth at any time, day and night, not limiting user's capacity talking on phone, to negotiate, drink water; (13) provide efficiency of manufacturing, eliminating the stages of lamination to backing film and incorporation of nonwoven mesh into adhesive layer, loaded with whitening agent.

DETAILED DESCRIPTION OF THE INVENTION

Before describing the present invention in detail, it is to be understood that unless otherwise indicated this invention is not limited to specific formulation materials or manufacturing processes, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. It must be noted that, as used in this 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 hydrophilic polymer" includes not only a single hydrophilic polymer but also a combination or mixture of two or more different hydrophilic polymers, reference to "a plasticizer" includes a combination or mixture of two or more different plasticizers as well as a single plasticizer, and the like.

In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below.

The polymers accepting protons in the course of hydrogen bonding with macromolecules containing complementary functional groups have been defined here as polybases.

In contrast, the polymers donating protons in the course of hydrogen bonding with macromolecules containing complementary functional groups have been defined here as polyacids.

The definitions of "hydrophobic" and "hydrophilic" polymers are based on the amount of water vapor absorbed by polymers at 100 % relative humidity. According to this classification, hydrophobic polymers absorb only up to 1 wt. % water at 100% relative humidity ("RH"), while moderately hydrophilic polymers absorb 1 -10 wt. % water, hydrophilic polymers are capable of absorbing more than 10 wt. % of water, and hygroscopic polymers absorb more than 20 wt. % of water. A "water-swellable" polymer is one that absorbs an amount of water greater than at least 50 wt.% of its own weight, upon immersion in an aqueous medium.

The term "crosslinked" herein refers to a composition containing intramolecular and/or intermolecular crosslinks, whether arising through covalent or noncovalent bonding. "Noncovalent" bonding includes both hydrogen bonding and electrostatic (ionic) bonding.

The term "polymer" includes linear and branched polymer structures, and also encompasses crosslinked polymers as well as copolymers (which may or may not be crosslinked), thus including block copolymers, alternating copolymers, random copolymers, and the like. Those compounds referred to herein as "oligomers" are polymers having a molecular weight below about 1000 Da, preferably below about 800 Da.

The term "film-forming hydrophilic polymer" refers to a polymer with a plurality of recurring polar groups thereon. In the composition of invention, the film-forming polymer is present in a higher concentration than each of others composition components, and it is this higher concentration that determines the film-forming characteristics.

While a film-forming polymer (FFP) is a major polymeric component of the composition of invention, its complementary counterpart, capable of noncovalent crosslinking of the FFP through hydrogen or electrostatic bonds, is defined as a "non- covalent crosslinker" (NCC). The NCC presents in the composition in a lower concentration than the FFP, although both polymeric components may belong to the same class of hydrophilic polymers. The ratio between the concentrations of the FFP and NCC (FFP:NCC) determines the density of noncovalent network and entire range of physical properties, including mechanical properties, solubility, swelling and adhesion of the polymer composition.

The term "hydrogel" is used in the conventional sense to refer to water-swellable polymeric matrices that can absorb a substantial amount of water to form elastic gels, where the "matrices" are three-dimensional networks of macromolecules held together by covalent or non-covalent crosslinks. Upon placement in an aqueous environment, dry hydrogels swell to the extent allowed by the degree of cross-linking. Hydrogels are generally water insoluble, but are able to be partly water soluble, or to dissolve gradually in water soluble.

The term "hydrogel composition" refers to a composition that either contains a hydrogel or is entirely composed of a hydrogel. As such, "hydrogel compositions" encompass not only hydrogels per se but also compositions that comprise a hydrogel and one or more non-hydrogel components or compositions.

The terms "tack" and "tacky" are qualitative. However, the terms "substantially nontacky," "slightly tacky," and "tacky," as used herein, may be quantified using the values obtained in a PKI tack determination, a TRBT tack determination, or a PSA tack determination/Polyken Probe (Solutia, Inc.). The term "substantially nontacky" is used to refer to a composition having a tack value less than about 25 g-cm/sec, the term "slightly tacky" refers to a composition having a tack value in the range of about 25 g-cm/sec to about 100 g-cm/sec, and the term "tacky" refers to a composition having a tack value of at least 100 g-cm/sec.

The term "plasticizer" is used in the conventional sense of the term to refer to a relatively low molecular weight compound that is miscible with a polymer or polymer blend and decreases the glass transition temperature and elastic modulus thereof.

The term "pressure sensitive adhesive" (PSA) relates to the polymer materials, which form a strong adhesive bond to any surface with application of very slight external pressure (1-10 Pa) over a short period of time (e.g., 1-5 seconds).

The term "bioadhesive" means a hydrogel that exhibits a pressure-sensitive character of adhesion toward highly hydrated surfaces such as mucosal biological tissue. In dry state classical bioadhesives possess no or negligible adhesion towards dry substrates, but become tacky upon absorbance of significant amounts of moisture.

The term "targeted (or selective) adhesion towards teeth" implies here a strong adhesion towards tooth surface and the lack of any adhesion towards other biological tissues in oral cavity, such as tongue, lips, gingiva, palate, and buccal mucosa.

The term "cohesion" refers to the intermolecular attraction between like or complementary, self-associating macromolecules. The driving force of an intermolecular cohesion are hydrogen, electrostatic and/or ionic bonding between the complementary macromolecules. In polymer composite materials the long chain entanglements serve as an additional factor contributing to high cohesive strength.

Some polymers bearing attractive groups are called "smart", "intelligent" or "stimuli-sensitive" since they show critical phenomena as, for example, phase transitions that can be induced by external stimuli: changes in temperature, pH, solvent, ionic composition, electric or magnetic fields, light, etc. The PSAs can be considered as "smart" materials because they possess different adhesion towards different substrates.

The term "complex" or "interpolymer complex" refers to the association of macromolecules of two or more complementary polymers that forms as a result of favorable interactions between their functional groups.

In interpolymer complexes the high cohesion energy is due to the formation of ionic, electrostatic or hydrogen bonds crosslinking the polymer chains into network. Hydrogen bonding is substantially weaker than electrostatic or ionic bonding, whereas ionic bonds are much weaker than covaient bonds. Nevertheless, comparatively weak intermolecular bonds have appreciable advantage over the strong covaient bonds with respect to mechanical strength and adhesion of polymer blend. Being once ruptured, the covaient bond is incapable to reform. In contrast, the ionic, electrostatic and hydrogen bonds have temporary character and demonstrate the capability of rearrangement and reformation at a new place under applied mechanical or debonding stress. As a result, viscoelastic deformation and debonding of the PSA networks involving the ionic, electrostatic and hydrogen bonding can dissipate much more mechanical energy than in covalently crosslinked adhesives. Thus, non-permanent nature of comparatively weaker molecular interaction contributes significantly to the strength of adhesive bond.

Interpolymer complexes are noncovalently crosslinked three-dimensional polymer networks (gels) resulting from ionic, electrostatic or hydrogen bonding between complementary functional groups in their macromolecules. If both complementary polymers contain ionogenic functional groups, their association product is termed polyelectrolyte complex. A distinctive feature of "hydrogen bonding" between proton donating and proton accepting complementary groups is that both the reactive groups and the product of their interaction bear no electric charge. "Electrostatic bonding" is the interaction of proton donating and proton accepting groups, which are initially uncharged, but their interaction is accompanied with proton transfer and occurrence of the charge. And lastly, "ionic bonding" is the interaction of oppositely charged (cationic and anionic) groups with the formation of ionic (salt) bond.

For the purposes of present invention it is very important that general property of interpolymer complexes is their insolubility in aqueous media, even in that case, when parent polymers are easily soluble. At the same time, usually the interpolymer complexes are capable of gradual swelling in water. In the swollen state they become slowly soluble, fully or partly. The soluble part of the interpolymer complexes is defined as the sol fraction. Insoluble part of the interpolymer complexes is known as the gel fraction.

The term "free volume" of a polymer is used to define the unoccupied space, or vacancies, available for segmental motion of macromolecules. The free volume of a material is the difference between the bulk volume and the sum of the hard core and vibrational volumes of the constituent building blocks (atoms). In polymer physics the free volume concept has long been used to interpret and explain the molecular mobility of the macromolecules along with such fundamental properties and quantities as the glass transition and glass transition temperature, viscoelastic, adhesion and relaxation behaviors, diffusion, and other transport properties of polymer systems. Along with the energy of intermolecular cohesion, free volume is a factor controlling the values of cohesive energy density, solubility parameter and the Flory-Huggins interaction parameter.

The pressure sensitive bio-adhesive compositions described in present invention can be employed as solid films, hydrogels and liquid solutions. Correspondingly, the adhesive films can be either gradually soluble in saliva in the course of their application to teeth, or insoluble. Insoluble films should be removed from the teeth and are defined further as strips.

It is desirable to obtain a water-swellable, water-insoluble or gradually dissolving in saliva bio-PSA hydrogel composition for sustained release of one or few tooth- whitening agents that strongly adheres to a surface of teeth but remains nontacky towards tongue and others mucosal tissues in oral cavity. The compositions should be applicable to teeth either in the form of viscous gel or as tooth whitening one-layer transparent or translucent strip.

The thermodynamic model of adhesion, generally attributed to Sharpe and

Schonhorn (L. H. Sharpe and H. Schonhorn, Chem. Eng. News 1963, vol. 15, 67), is the most widely used approach in adhesion science at present. This theory is based on the belief that the adhesive will adhere to the substrate because of interatomic and intermolecular forces established at the interface, provided that an intimate contact is achieved. The most common interfacial forces result from van der Waals and Lewis acid - base interactions. The magnitude of these forces can generally be related to fundamental thermodynamic quantities, such as surface free energies of both adhesive and adherend. Generally, the formation of an assembly goes through a liquid-solid contact step, and therefore criteria of good adhesion become essentially criteria of good wetting, although this is a necessary but not sufficient condition. Hydrogen and electrostatic bonds formed between functional groups of PSA composition and tooth enamel appreciably contribute to the strength of their adhesive joint.

The major component of dental enamel is hydroxylapatite, also called hydroxyapatite (HA). The HA is a naturally occurring mineral form of calcium apatite with the formula Ca₅(P0₄)₃(OH), but is usually written Ca₁₀(PO₄)₆(OH)₂ to denote that the crystal unit cell comprises two entities. The Orf ion in the HA can be replaced by fluoride, chloride or carbonate anions, producing fluorapatite (FA), chlorapatite (ChA) or carbonate apatite (CA). The contents of HA, FA, ChA and CA in tooth enamel are 75, 0.66, 4.4 and 19 %, respectively. The presence of the hydroxyl ions in the enamel implies that the most strong specific (ionic) interfacial bonds with tooth surface, and, consequently, carboxyl containing polymers (i.e. polyacids) will provide adhesion towards dental enamel.

Polyacids suitable for their application in dental adhesives include poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), corresponding copolymers and blends therof. Other suitable carboxyl-containing polymers are hyaluronic acid, alginic acid and cellulose derivatives listed below.

Mineral salts are high surface energy materials, forming stronger adhesive bonds with polar (hydrophilic) polymers which possess high surface energy. The examples of suitable proton-donating polymers utilized as the basis for dental adhesives also include polyalcohols, polyphenols, and hydroxyl-containing cellulose derivatives, e.g. poly(vinyl alcohol), poly(vinyl phenol), hydroxyalkyl cellulose.

Because the CA in tooth enamel contains mobile proton in the hydrocyl anion, adhesion to teeth can be also provided by proton-accepting polymers (polybases), e.g. poly(acryl amides), polyvinyl amides), poly(vinyl lactams), aminogroup-containing acrylates, methacrylates, poly(vinyl amine) and chitosan.

The term "mucoadhesion" was coined for the adhesion of the polymers with the surface of the mucosal layer. The mucosal layer is made up of mucus which is secreted by the goblet cells (glandular columnar epithelial cells) and is a viscoelastic fluid. It lines the visceral organs, which are exposed to the external environment. The main components constituting the mucosa include water and mucin (an anionic polyelectrolyte), while the other components include proteins, lipids and mucopolysaccharides. Water and mucin constitute > 99% of the total composition of the mucus and out of this > 95% is water. The gel-like structure of the mucus can be attributed to the intermolecular entanglements of the mucin glycoproteins along with the non-covalent interactions (e.g. hydrogen, electrostatic and hydrophobic bonds) which results in the formation of a hydrated gel-like structure and explains the viscoelastic nature of the mucus (S. Roy, K. Pal, A. Anis, K. Pramanik, B.Prabhakar, Polymers in Mucoadhesive Drug Delivery System: A Brief Note, Designed Monomers and Polymers 2009, 12, 483 - 495).

Formation of hydrogen-bonds amongst the functional groups of the polymers and mucosal layer plays an important role. In general, stronger the hydrogen bonding stronger is the adhesion. The functional groups responsible for such kind of interaction include hydroxyl, carboxyl and amino groups. Various polymers which have the ability to form strong hydrogen bonds include poly (vinyl alcohol), acrylic derivates, celluloses and starch. Apart from the hydrogen bond formation, the presence of functional groups within the polymer structure may render the polymer chains as polyelectrolytes. The presence of charged functional groups in the polymer chain has a marked effect on the strength of the bioadhesion. Anionic polyelectrolytes have been found to form stronger adhesion when compared with neutral polymers. The various mucoadhesive polymers used for the development of buccal drug delivery systems include cyanoacrylates, polyacrylic acid, sodium carboxymethylcellulose, hyaluronic acid, hydroxypropylcellulose, polycarbophil, chitosan and gellan.

Diverse classes of polymers have been investigated for potential use as mucoadhesives. These include synthetic polymers such as poly(acrylic acid) (PAA), hydroxypropyl methylcellulose and poly(methylacrylate) derivatives, as well as naturally occurring polymers such as hyaluronic acid and chitosan. Among these various possible bioadhesive polymeric hydrogels, PAA has been considered as a good mucoadhesive. However, due to a high glass transition temperature and higher interfacial free energy, PAA does not wet the mucosal surface to the optimal level, causing loose interpenetration and interdiffusion of the polymer. Therefore, PAA is copolymerised with polyethylene glycol (PEG) or poly(vinyl pyrrolidone) (PVP) to improve these properties (B. Jasti, X. Li, G. Cleary, Recent Advances in Mucoadhesive Drug Delivery Systems, Busyness Briefing: PHARMATECH 2003, 194 - 196). The strong adhesion of carboxyl - containing polyacids to the mucin based on anionic polyelectrolyte is apparently unexpected result, which can be explained by the capability of carboxyl groups to form very stable self- associates.

Thus, despite dental enamel and mucin have dissimilar chemical compositions and structures, the same polymer classes can be employed as the platforms for both tooth and mucosal bioadhesives. In this connection, in which manner can be provided the selectivity of polymer adhesion towards diverse biological substrates in oral cavity?

Pertinently to mention, that the adhesive - substrate interaction represents only one mechanism responsible for pressure sensitive adhesion. Another relevant mechanism of the adhesion is a competition between mechanical properties of the adhesive and the substrate. In fact, as has been recently shown by Feldstein, 180° Peel force, P, required to rupture adhesive bond of soft PSA with hard substrate relates to the bulky PSA properties by Equation (1):

where k is a constant taking into account interfacial adhesive - substrate interaction, b and / are the width and thickness of adhesive layer, N is the number of segments of size a in the polymer chain, D is the self diffusion coefficient of the polymer segment, r is the PSA relaxation time, k_H is Boltzmann's constant, T is temperature (K), and σ¾ is the ultimate tensile stress of PSA film under uniaxial stretching up to break (see M.M. Feldstein, R.A. Siegel, Molecular and Nanostructural Factors Governing Pressure Sensitive Adhesion Strength of Viscoelastic Polymers, J. Polym. Sci., Polym. Phys. Ed., 2012, in press). The is a measure of PSA material cohesive strength, while the factor underlying the value of self-diffusion coefficient D at a molecular level relates to a free volume available for self-diffusion of polymer chain. The implication of Equation (1) is that the high adhesive strength of PSA polymer is the result of compromise between two mutually conflicting properties, the high molecular mobility controlled by large free volume, and the strong intermolecular cohesion energy, governing the PSA cohesive strength.

In view of Equation (1), the targeted "smart" polymer adhesion to dental enamel in oral cavity results from the dissimilarity in mechanical properties of the substrates. High adhesion requires the formation of good adhesive contact that can be achieved between soft adhesive and rigid substrate. As the adhesive is harder than the substrate, the good adhesive contact and the high adhesion are unattainable. Teeth are the rigid substrate, whereas tongue, gums and other mucosal tissues are the soft substrates. In this way, the hardness of different tissues in oral cavity provides a major tool by means of which the "smart" bio-PSA in the mouth recognizes its target substrate.

Another fundamental problem underlying the formulation and the production of tooth whitening gels and strips is a compatibility of bio-PSA platform with a whitening agent. The hydrogen peroxide decomposition occurs more rapidly in alkaline aqueous solutions, so acid is often added as a stabilizer. In contrast, in solid state the hydrogen peroxide is stabilized by H-bond complex formation with proton-accepting polymers and low molecular weight substances (e.g. poly(N-vinyl pyrrolidone), urea, sodium carbonate( see C.W. Jones, Applications of Hydrogen Peroxide and Derivatives, The Royal Society of Chemistry, Cambridge, 1999), but decomposes in presence of water, acids and other proton-donating functionalities (see J.A. Dobado, J. Molina, D. Portal, Theoretical Study on the Urea-Hydrogen Peroxide 1:1 Complexes, J. Phys. Chem. A 1998, 102, 778-784). Because carboxyl-containing polymers used in "smart" bio-PSA platforms induce hydrogen peroxide degradation, our approach to production of tooth- whitening systems is based on following methods:

1) Mixing the formulation components in a dry (molten) state using a single or twin extruder;

2) An interlock of the proton-donating functional groups of a film-forming polymer by their complexation with complementary proton-accepting functional groups of a low or high molecular weight protector prior to the hydrogen peroxide is incorporated into a casting solution.

As the carbamide peroxide is employed, under temperature elevation the complex melting occurs in the range of 88 - 92 °C, and the decomposition proceeds at the temperature above 115 ⁰ C.

As the whitening agent is the sodium carbonate peroxide, thermodesorption of the hydrogen peroxide takes a place above 74 ⁰ C, and the decomposition occurs above 142 ⁰ C.

As the components of tooth whitening system are mixed in solution, the carboxyl containing polymer should be first mixed with a complementary stabilizer of the hydrogen peroxide to interlock the carboxyl protons by hydrogen bonding and the whitening agent has to be added last.

Suitable hydrogen peroxide stabilizers in this case are proton accepting polymers and low molecular weight compounds, which include, without any limitation, homo- and copolymers of N-vinyl lactams, acrylamides, polyurethanes, polyurea, polypeptides, and the low molecular weight urea.

In tooth whitening compositions of the invention a single whitening agent can be employed or the combination thereof.

In a first embodiment, a tooth whitening formulation is provided that comprises a first tooth whitening agent that is inert in a dry environment but activated in the presence of moisture to release peroxide and produce an alkaline pH, a second tooth whitening agent that releases peroxide rapidly upon contact with moisture in the presence of base, and at least one water-swellable, water-insoluble polymer. The first tooth whitening agent may be, for example, an addition compound of (a) a salt of an oxyanion and (b) hydrogen peroxide. Such tooth whitening agents include, without limitation, sodium percarbonate (2Na₂C0₃ 3H₂0₂; also known as sodium carbonate peroxyhydrate and peroxy sodium carbonate), which breaks down to sodium carbonate and hydrogen peroxide in water, with a resultant increase in the pH of the solution. Such tooth whitening agents also include sodium perborate (NaB0₃), sodium perborate monohydrate, and sodium perborate tetrahydrate. The second tooth whitening agent may be, for example, carbamide peroxide (CO(NH₂)₂-H₂0₂; also known as urea peroxide, Urea peroxide (Percarbamide); Hydrogen peroxide compounded with urea (1:1); Hydroperit; Hyperol; Ortizon; Perhydrit; Perhydrol-urea; Thenardol; Urea compounded with hydrogen peroxide (1:1); Urea Hydroperoxide), or selected from any number of other organic and inorganic compounds that release peroxide rapidly in the presence of aqueous base.

The water-swellable, water-insoluble polymer is capable of at least some degree of swelling when immersed in an aqueous liquid but is either completely insoluble in water or water-insoluble within a selected pH range, generally up to a pH of at least about 7.5 to 8.5. The polymer may be comprised of a cellulose ester, for example, cellulose acetate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP), cellulose butyrate (CB), cellulose propionate butyrate (CPB), cellulose diacetate (CDA), cellulose triacetate (CTA), or the like. Cellulose esters are described in U.S. Patent Nos. 1,698,049, 1 ,683,347, 1 ,880,808, 1 ,880,560, 1,984,147, 2,129,052, and 3,617,201 , and may be prepared using techniques known in the art or obtained commercially. Commercially available cellulose esters suitable herein include CA 320, CA 398, CAB 381, CAB 551 , CAB 553, CAP 482, CAP 504, all available from Eastman Chemical Company, Kingsport, Tenn. Such cellulose esters typically have a number average molecular weight of between about 10,000 and about 75,000.

Generally, cellulose esters comprise a mixture of cellulose and cellulose ester monomer units; for example, commercially available cellulose acetate butyrate contains cellulose acetate monomer units as well as cellulose butyrate monomer units and unesterified cellulose units. Preferred cellulose esters herein are cellulose acetate butyrate compositions and cellulose acetate propionate compositions with the following properties: cellulose acetate butyrate, butyrate content 17-52%, acetyl content 2.0-29.5%, unesterified hydroxyl content, 1.1 -4.8%, molecular weight 12,000-20,000 g/mole, glass transition temperature T_g in the range of 96-141°C, and melting temperature in the range of 130-240°C; and cellulose acetate propionate, propionate content 42.5-47.7%, acetyl content 0.6-1.5%, unesterified hydroxyl content, 1.7-5.0%, molecular weight 15,000- 75,000 g/mole, glass transition temperature T_g in the range of 142-159°C, and melting temperature in the range of 188-210°C. Suitable cellulosic polymers typically have an inherent viscosity (I. V.) of about 0.2 to about 3.0 deciliters/gram, preferably about 1 to about 1.6 deciliters/gram, as measured at a temperature of 25°C for a 0.5 gram sample in 100 ml of a 60/40 by weight solution of phenol/tetrachloroethane.

Other preferred water-swellable polymers are acrylate polymers, generally formed from acrylic acid, methacrylic acid, acrylate, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, a dialkylaminoalkyl acrylate, a dialkylaminoalkyl methacrylate, a trialkylammonioalkyl acrylate, and/or a trialkylammonioalkyl methacrylate. Preferred such polymers are copolymers of acrylic acid, methacrylic acid, methyl methacrylate, ethyl methacrylate, 2-dimethylaminoethyl methacrylate, and/or trimethylammonioethyl methacrylate chloride.

Suitable acrylate polymers are those copolymers available under the tradename

"Eudragit" from Rohm Pharma (Germany),, now «Evonik Industries » The Eudragit series E, L, S, RL, RS and NE copolymers are available as solubilized in organic solvent, in an aqueous dispersion, or as a dry powder. Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers. Particularly preferred such copolymers are Eudragit L-30D-55 and Eudragit L- 100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 that can be reconstituted with water). The molecular weight of the Eudragit L-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da, with a ratio of free carboxyl groups to ester groups of approximately 1 :1. The copolymer is generally insoluble in aqueous fluids having a pH below 5.5. Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which differs from Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is approximately 1 :2. Eudragit S-100 is insoluble at pH below 5.5, but unlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7.0. This copolymer is soluble at pH 7.0 and above. Eudragit L-100 may also be used, which has a pH-dependent solubility profile between that of Eudragit L-30D-55 and Eudragit S-100, insofar as it is insoluble at a pH below 6.0. It will be appreciated by those skilled in the art that Eudragit L-30D-55, L- 100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics.

Other preferred acrylate polymers are cationic, such as the Eudragit E, RS, and RL series polymers. Eudragit EIOO and E PO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates (e.g., methyl methacrylate), while Eudragit RS and Eudragit RL polymers are analogous polymers, composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate. In this embodiment, the formulation may contain a single water-swellable, water-insoluble polymer as described above. Alternatively, an admixture of at least two water-swellable, water-insoluble polymers may be present. In the latter case, an exemplary formulation is provided by combining a cationic water-swellable, water- insoluble polymer with an anionic water swellable, water-insoluble polymer, such that the polymers are ionically associated with each other and form a polymer matrix. For example, the cationic polymer may be an acrylate-based polymer with pendant quaternary ammonium groups or tertiary amino groups (as exemplified by a Eudragit RS , Eudragit RL, Eudragit E copolymer), and the anionic polymer may be an ionized acrylic acid or methacrylic acid polymer such as a Eudragit L or Eudragit S copolymer. The anionic polymer may also be, for example, hydroxypropyl methylcellulose phthalate.

The tooth whitening formulation will generally include a crosslinked hydrophilic polymer as well. The crosslinked hydrophilic polymer may be covalently crosslinked, ionically crosslinked, or crosslinked via hydrogen bonding, wherein crosslinking may be either intramolecular or intermolecular, and the formulations may contain any combinations of such crosslinked polymers. The hydrophilic polymer may be crosslinked via a crosslinking agent, e.g., via a low molecular weight complementary oligomer.

Suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer. Such polymers include, by way of example, poly(N-vinyl lactams), poly(N-vinyl acrylamides), poly(N-alkylacrylamides), substituted and unsubstituted acrylic and methacrylic acid polymers, polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof and copolymers with other types of hydrophilic monomers (e.g. vinyl acetate). Other suitable hydrophilic polymers include, but are not limited to: polysaccharides; crosslinked acrylate polymers and copolymers; carbomers, i.e., hydroxylated vinylic polymers (also referred to as "interpolymers") which are prepared by crosslinking a monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose (commercially available under the trademark Carbopol^® from the B. F. Goodrich Chemical Company); crosslinked acrylamide-sodium acrylate copolymers; gelatin; vegetable polysaccharides, such as alginates, pectins, carrageenans, or xanthan; starch and starch derivatives; and galactomannan and galactomannan derivatives.

Polysaccharide materials include, for instance, crosslinked, normally water- soluble cellulose derivatives that are crosslinked to provide water-insoluble, water- swellable compounds, such as crosslinked sodium carboxymethylcellulose (CMC), crosslinked hydroxyethyl cellulose (HEC), crosslinked partial free acid CMC, and guar gum grafted with acrylamide and acrylic acid salts in combination with divinyl compounds, e.g., methylene-bis acrylamide. Within the aforementioned class, the more preferred materials are crosslinked CMC derivatives, particularly crosslinked sodium CMC and crosslinked HEC. Other polysaccharides suitable herein include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and the like.

Poly(N-vinyl lactams) useful herein are preferably homopolymers or copolymers of N-vinyl lactam monomer units, with N-vinyl lactam monomer units representing the majority of the total monomeric units of a poly(N-vinyl lactams) copolymer. Preferred poly(N-vinyl lactams) for use in conjunction with the invention are prepared by polymerization of one or more of the following N-vinyl lactam monomers: N-vinyl-2- pyrrolidone; N-vinyl-2-valerolactam; and N-vinyl-2-caprolactam. Nonlimiting examples of non-N-vinyl lactam comonomers useful for copolymerzation with N-vinyl lactam monomeric units include Ν,Ν-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-l -propane sulfonic acid or its salt, and vinyl acetate.

Poly (N-alkylacrylamides) include, by way of example, poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM). Polymers of carboxy vinyl monomers are typically formed from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride, or mixtures thereof, with preferred hydrophilic polymers within this class including polyacrylic acid and polymethacrylic acid, with polyacrylic acid most preferred.

Preferred hydrophilic polymers herein are the following: poly(N-vinyl lactams), particularly polyvinyl pyrrolidone (PVP) and poly(N-vinyl caprolactam) (PVCap); poly(N-vinyl acetamides), particularly polyacetamide per se; polymers of carboxy vinyl monomers, particularly polyacrylic acid and polymethacrylic acid; and copolymers and blends thereof. PVP and PVCap are particularly preferred.

The molecular weight of the hydrophilic polymer is not critical; however, the number average molecular weight of the hydrophilic polymer is generally in the range of approximately 20,000 to 2,000,000, more typically in the range of approximately 200,000 to 1 ,000,000. Covalent crosslinking may be accomplished in several ways. For instance, the hydrophilic polymer, or the hydrophilic polymer and a complementary oligomer, may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent. Covalently crosslinked hydrophilic polymers may also be obtained commercially, for example, crosslinked sodium CMC is available under the tradename Aquasorb® (e.g., Aquasorb^® A500) from Aqualon, a division of Hercules, Inc., and crosslinked PVP is available under the tradename Kollidon^® (e.g., Kollidon^® CL, and Kollidon^® CL-M, a micronized form of crosslinked PVP, both available from BASF).

For thermal crosslinking, a free radical polymerization initiator is used, and can be any of the known free radical-generating initiators conventionally used in vinyl polymerization. Preferred initiators are organic peroxides and azo compounds, generally used in an amount from about 0.01 wt.% to 15 wt.%, preferably 0.05 wt.% to 10 wt.%, more preferably from about 0.1 wt.% to about 5% and most preferably from about 0.5 wt.% to about 4 wt.% of the polymerizable material. Suitable organic peroxides include dialkyl peroxides such as t-butyl peroxide and 2,2 bis(f-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as ?-butyl perbenzoate and /-butyl per-2-ethylhexanoate, perdi carbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methyl ethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert-butyl\ hydroperoxide. Suitable azo compounds include azo bis (isobutyronitrile) and azo bis (2,4-dimethylvaleronitrile). The temperature for thermal crosslinking will depend on the actual components and may be readily determined by one of ordinary skill in the art, but typically ranges from about 80 °C to about 200 °C.

Crosslinking may also be accomplished with radiation, typically in the presence of a photoinitator. The radiation may be ultraviolet, alpha, beta, gamma, electron beam, and x-ray radiation, although ultraviolet radiation is preferred. Useful photosensitizers are triplet sensitizers of the "hydrogen abstraction" type, and include benzophenone and substituted benzophenone and acetophenones such as benzyl dimethyl ketal, 4- acryloxybenzophenone (ABP), 1 -hydroxy-cyclohexyl phenyl ketone, 2,2- diethoxyacetophenone and 2,2-dimethoxy-2-phenylaceto-phenone, substituted alpha- ketols such as 2-methyl-2-hydroxypropiophenone, benzoin ethers such as benzoin methyl ether and benzoin isopropyl ether, substituted benzoin ethers such as anisoin methyl ether, aromatic sulfonyl chlorides such as 2-naphthalene sulfonyl chloride, photoactive oximes such as 1-phenyl- 1 ,2-propanedione-2-(0- ethoxy-carbonyl)-oxime, thioxanthones including alkyl- and halogen-substituted thioxanthonse such as 2-isopropylthioxanthone, 2-chlorothioxanthone, 2,4 dimethyl thioxanone, 2,4 dichlorothioxanone, and 2,4-diethyl thioxanone, and acyl phosphine oxides. Radiation having a wavelength of 200 to 800 nm, preferably, 200 to 500 nm, is preferred for use herein, and low intensity ultraviolet light is sufficient to induce crosslinking in most cases. However, with photosensitizers of the hydrogen abstraction type, higher intensity UV exposure may be necessary to achieve sufficient crosslinking. Such exposure can be provided by a mercury lamp processor such as those available from PPG, Fusion, Xenon, and others. Crosslinking may also be induced by irradiating with gamma radiation or an electron beam. Appropriate irradiation parameters, i.e., the type and dose of radiation used to effect crosslinking, will be apparent to those skilled in the art.

Suitable chemical curing agents, also referred to as chemical cross-linking "promoters," include, without limitation, polymercaptans such as 2,2-dimercapto diethylether, dipentaerythritol hexa(3-mercaptopropionate), ethylene bis(3- mercaptoacetate), pentaerythritol tetra(3-mercapto propionate), pentaerythritol tetrathioglycolate, polyethylene glycol dimercaptoacetate, polyethylene glycol di(3- mercaptopropionate), trimethylolethane tri(3-mercaptopropionate), trimethylolethane trithioglycolate, trimethylolpropane tri(3-mercapto-propionate), trimethylolpropane trithioglycolate, dithioethane, di- or trithiopropane and 1 ,6-hexane dithiol. The crosslinking promoter is added to the uncrosslinked hydrophilic polymer to promote covalent crosslinking thereof, or to a blend of the uncrosslinked hydrophilic polymer and the complementary oligomer, to provide crosslinking between the two components.

The crosslinked hydrophilic polymer may also comprise a blend of a hydrophilic polymer and a low molecular weight complementary oligomer capable of crosslinking the polymer via hydrogen bonding. In this case, the hydrophilic polymer may or may not be crosslinked prior to admixture with the complementary oligomer. If the hydrophilic polymer is crosslinked prior to admixture with the complementary oligomer, it may be preferred to synthesize the polymer in crosslinked form, by admixing a monomelic precursor to the polymer with multifunctional comonomer and copolymerizing. Examples of monomelic precursors and corresponding polymeric products are as follows: N-vinyl amide precursors for a poly(N-vinyl amide) product; N-alkylacrylamides for a poly(N- alkylacrylamide) product; acrylic acid for a polyacrylic acid product; methacrylic acid for a polymethacrylic acid product; acrylonitrile for a poly(acrylonitrile) product; and N- vinyl pyrrolidone (NVP) for a poly(vinylpyrrolidone) (PVP) product. Polymerization may be carried out in bulk, in suspension, in solution, or in an emulsion. Solution polymerization is preferred, and polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred. For preparation of hydrophilic vinyl polymers, synthesis will typically take place via a free radical polymerization process in the presence of a free radical initiator as described above. The multifunctional comonomer include, for example, bisacrylamide, acrylic or methacrylic esters of diols such as butanediol and hexanediol (1,6-hexane diol diacrylate is preferred), other acrylates such as pentaerythritol tetraacrylate, and 1,2-ethylene glycol diacrylate, and 1 ,12-dodecanediol diacrylate. Other useful multifunctional crosslinking monomers include oligomeric and polymeric multifunctional (meth)acrylates, e.g., poly(ethylene oxide) diacrylate or poly(ethylene oxide) dimethacrylate; polyvinylic crosslinking agents such as substituted and unsubstituted divinylbenzene; and difunctional urethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (1500 weight average molecular weight and 5000 weight average molecular weight acrylated urethanes, respectively— both available from UCB of Smyrna, Ga.), and combinations thereof. If a chemical crosslinking agent is employed, the amount used will preferably be such that the weight ratio of crosslinking agent to hydrophilic polymer is in the range of about 1 : 100 to 1 :5. To achieve a higher crosslink density, if desired, chemical crosslinking is combined with radiation curing.

If the crosslinked hydrophilic polymer is in the form of a blend of a hydrophilic polymer and a low molecular weight complementary oligomer, the blend will usually provide a matrix that is crosslinked solely by hydrogen bonds formed between the termini of the oligomer and pendant groups on the hydrophilic polymer. In this embodiment, suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer, as described above with regard to crosslinked hydrophilic polymers per se, and preferred hydrophilic polymers in this blend are also as described above for those polymers.

The oligomer is generally "complementary" to the hydrophilic polymers in that it is capable of hydrogen bonding thereto. Preferably, the complementary oligomer is terminated with hydroxyl groups, amino or carboxyl groups. The oligomer typically has a glass transition temperature T_g in the range of about -100°C to about -30°C and a melting temperature T_m lower than about 20°C. The oligomer may be also amorphous. The difference between the T_g values the hydrophilic polymer and the oligomer is preferably greater than about 50 °C, more preferably greater than about 100 °C, and most preferably in the range of about 150°C to about 300°C. The hydrophilic polymer and complementary oligomer should be compatible, i.e. capable of forming a homogeneous blend that exhibits a single T_g, intermediate between those of the unblended components. Generally, the oligomer will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600. Examples of suitable oligomers include, but are not limited to, low molecular weight polyalcohols (e.g. glycerol), oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol, and carboxyl -terminated and amino-terminated derivatives of polyalkylene glycols. Polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal complementary oligomer.

The hydrophilic polymer and the complementary oligomer should be miscible with respect to each other and have disparate chain lengths (as may be deduced from the above). The ratio of the average molecular weight of the hydrophilic polymer to that of the oligomer should be within about 200 and 200,000, preferably within about 1 ,250 and 20,000. Also, the polymer and the oligomer should contain complementary functional groups capable of hydrogen bonding, ionically bonding, or covalently bonding to each other. Ideally, the complementary functional groups of the polymer are located throughout the polymeric chains, while the functional groups of the oligomer are preferably located at the two termini of a linear molecule, and are not present along the backbone. Forming hydrogen bonds or ionic bonds between the two terminal functional groups of the oligomer and the corresponding functional groups contained along the backbone of the hydrophilic polymer results in a noncovalently linked supramolecular network.

As discussed in U.S. Patent No. 6,576,712 to Feldstein et al., the ratio of the hydrophilic polymer to the complementary oligomer in the aforementioned blend affects both adhesive strength and cohesive strength. As explained in the aforementioned patent, the complementary oligomer decreases the glass transition of the hydrophilic polymer/complementary oligomer blend to a greater degree than predicted by the Fox equation, which is given by equation (2) 1

(2)

T g, predicted

where T_g predicted is the predicted glass transition temperature of the hydrophilic polymer/complementary oligomer blend, w_poi is the weight fraction of the hydrophilic polymer in the blend, w_p\ is the weight fraction of the complementary oligomer in the blend, T_{g po}i is the glass transition temperature of the hydrophilic polymer, and T_gpt is the glass transition temperature of the complementary oligomer. As also explained in that patent, an adhesive composition having optimized adhesive and cohesive strength can be prepared from a hydrophilic polymer and a complementary oligomer by selecting the components and their relative amounts to give a predetermined deviation from T_g pre icted - Generally, to maximize .adhesion, the predetermined deviation from T_g predicted will be the maximum negative deviation, while to minimize adhesion, any negative deviation from T_g predicted is minimized. Optimally, the complementary oligomer represents approximately 25 wt.% to 75 wt. , preferably about 30 wt.% to about 60 wt.%, of the hydrophilic polymer/complementary oligomer blend, and, correspondingly, the hydrophilic polymer represents approximately 75 wt.% to 25 wt.%, preferably about 70 wt.% to about 40 wt.%, of the hydrophilic polymer/oligomer blend.

For certain applications, particularly when a relatively high cohesive strength formulation is desired, the hydrophilic polymer, and optionally the complementary oligomer should be covalently crosslinked. The hydrophilic polymer may be covalently crosslinked, either intramolecularly or intermolecularly, and/or the hydrophilic polymer and the complementary oligomer may be covalently crosslinked. In the former case, there are no covalent bonds linking the hydrophilic polymer to the complementary oligomer, while in the latter case, there are covalent crosslinks binding the hydrophilic polymer to the complementary oligomer. The hydrophilic polymer, or the hydrophilic polymer and the complementary oligomer, may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent. The degree of crosslinking should be sufficient to eliminate or at least minimize cold flow under compression.

For covalently crosslinked hydrophilic polymer/complementary oligomer systems, the oligomer should be terminated at each end with a group capable of undergoing reaction with a functional group on the hydrophilic polymer. Such reactive groups include, for example, hydroxyl groups, amino groups, and carboxyl groups. These difunctionalized oligomers may be obtained commercially or readily synthesized using techniques known to those of ordinary skill in the art and/or described in the pertinent texts and literature.

As the complementary oligomer may itself act as a plasticizer, it is not generally necessary to incorporate an added low molecular weight plasticizer into the present compositions unless the optional complementary oligomer is not included. Suitable low molecular weight plasticizers include: dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates, and mixed alkyl-aryl phthalates, as represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate; alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, tricresyl phosphate, and triphenyl phosphate; alkyl citrate and citrate esters such as trimethyl citrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, and trihexyl citrate; dialkyl adipates such as dioctyl adipate (DOA; also referred to as bis(2- ethylhexyl)adipate), diethyl adipate, di(2-methylethyl)adipate, and dihexyl adipate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; dialkyl sebacates such as diethyl sebacate, dipropyl sebacate and dinonyl sebacate; dialkyl succinates such as diethyl succinate and dibutyl succinate; alkyl glycolates, alkyl glycerolates, glycol esters and glycerol esters such as glycerol diacetate, glycerol triacetate (triacetin), glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate; and mixtures thereof. Preferred low molecular weight plasticizers for the continuous hydrophilic phase are triethyl citrate, diethyl phthalate, and dioctyl adipate, with dioctyl adipate most preferred.

The properties of the compositions of the invention are readily controlled by adjusting one or more parameters during formulation. For example, the adhesiveness of the composition can be controlled during manufacture in order to increase or decrease the degree to which the composition will adhere to the teeth in the presence of moisture. This can be accomplished by varying type and/or amount of different components, or by changing the mode of manufacture. Also, with respect to the fabrication process, compositions prepared using a conventional melt extrusion process are generally, although not necessarily, somewhat less tacky than compositions prepared using a solution cast technique.

As has been mentioned above, for preparation of "smart" bioadhesive demonstrating strong adherence to teeth but no mucoadhesion to tongue, gums and palate, the chemical composition of adhesive tooth whitening formulation is of much less importance than its mechanical properties. In other words, the hydroactivated tackiness is mandatory but insufficient requirement of targeted adhesion to teeth in oral cavity. "Intelligent" adhesive in swollen state should be much softer than the tooth, but appreciably harder the mucosal tissues.

If adhesive hydrogel is softer than such rigid substrate as tooth, under slight external pressure provided by touch with finger it behaves like a liquid, spreading onto teeth surface and forming perfect adhesive contact. Covalent or noncovalent crosslinked structure of the adhesive hydrogel offers elasticity and enhances the resistance to detaching force, rendering the strength of adhesive joint with dental surface.

At the same time, as the dental adhesive in the swollen state is harder than mucosal membranes, it does not fit to oral mucosa and forms poor adhesive contact. In this case the adhesive hydrogel demonstrates no adhesion towards tongue, gingivae, inner cheek surface and palate.

To meet these requirements, the "smart" adhesive hydrogel should manifest strictly specified softness, evaluated in terms of dynamic elasticity modulus, G', and loss tangent, tan δ. Preferably, the G' value is below 0.45 MPa, and the loss tangent is within the range from 0.60 to 1.20. At most fundamental, molecular level, mechanical properties of materials are governed by the cohesion energy : free volume ratio, embedded by the glass transition temperature. In the swollen state the adhesive hydrogel should possess the Tg values ranged between -10 and -130 °C.

In another embodiment, a tooth whitening composition is provided that is composed of an admixture of a tooth whitening agent, generally, although not necessarily, one that is inert in a dry environment but activated in the presence of moisture, and at least two water-swellable, water-insoluble polymers, wherein a first water-swellable, water-insoluble polymer is cationic, a second water-swellable, water-insoluble polymer is anionic, and the polymers are ionically associated with each other to form a polymer matrix. In this embodiment, the composition may contain a single tooth whitening agent, but necessarily includes a mixture of ionically associated polymers as are present in the preferred embodiment discussed above. The cationic polymer may be, for example, an acrylate-based polymer with pendant quaternary ammonium groups, and the anionic polymer may be an ionized acrylic acid or methacrylic acid polymer. Specific such polymers are as described earlier herein.

In an additional embodiment, a tooth whitening composition is provided that is composed of an admixture of: 1.5 wt.% to 30 wt. , preferably 1.5 wt.% to 20 wt.%, more preferably 1.5 wt.% to 90 wt.%, and most preferably 1.5 wt.% to 95 wt.%, of a hydrophilic polymer composition composed of (a) a covalently crosslinked hydrophilic polymer, and/or (b) a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding thereto; 40 wt.% to 90 wt.%, preferably 45 wt. to 90 wt.%, more preferably 50 wt.% to 90 wt.%, and most preferably 60 wt.% to 90 wt.%, of at least one water-swellable, water-insoluble polymer; and at least one tooth whitening agent.

In these embodiments, suitable tooth whitening agents include peroxides, metal chlorites (e.g., calcium chlorite and sodium chlorite), perborates (e.g., sodium perborate), percarbonates (e.g., sodium percarbonate), peroxyacids (e.g., diperoxydodecanoic acid), and combinations thereof. Peroxides are preferred; representative peroxides include hydrogen peroxide, calcium peroxide, carbamide peroxide, dialkyl peroxides such as /- butyl peroxide and 2,2 bis(/-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as /-butyl perbenzoate and /-butyl per-2- ethylhexanoate, perdicarbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methylethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert- butyl hydroperoxide.

The tooth whitening compositions of the invention may include any of a number of optional additives, such as anti-tartar agents, enzymes, flavoring agents, sweeteners, fillers, preservatives, and breath fresheners.

Anti-tartar agents include phosphates such as pyrophosphates, polyphosphates, polyphosphonates (e.g., ethane- 1 -hydroxy- 1 ,1-diphosphonate, 1-azacycloheptane-l ,1- diphosphonate, and linear alkyl diphosphonates), and salts thereof; linear carboxylic acids; and sodium zinc citrate; and mixtures thereof. Preferred pyrophosphate salts are the alkali metal pyrophosphate salts and the hydrated or unhydrated forms of disodium dihydrogen pyrophosphate (Na₂H₂P₂0₇), tetrasodium pyrophosphate (Na₄P₂0₇), and tetrapotassium pyrophosphate (ί Ρ₂0₇). Anti-tartar agents also include betaines and amine oxides, as described in U.S. Patent No. 6,315,991 to Zofchak.

Enzymes useful in inhibiting the formation of plaque, calculus, or dental caries are also useful in the compositions. Such enzymes include: proteases that break down salivary proteins which are absorbed onto the tooth surface and form the pellicle, or first layer of plaque; lipases which destroy bacteria by lysing proteins and lipids which form the structural component of bacterial cell walls and membranes; dextranases, glucanohydrolases, endoglycosidases, and mucinases which break down the bacterial skeletal structure which forms a matrix for bacterial adhesion to the tooth; and amylases which prevent the development of calculus by breaking-up the carbohydrate- protein complex that binds calcium. Preferred enzymes include any of the commercially available proteases; dextranases; glucanohydrolases; endoglycosidases; amylases; mutanases; lipases; mucinases; and compatible mixtures thereof.

Any natural or synthetic flavorants can be used. Suitable flavorants include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils, and oleoresins, as known in the art, as well as combinations thereof. The amount of flavorant employed is normally a matter of preference, subject to such factors as flavor type, individual flavor, and strength desired. Preferably, the composition comprises from about 0.1 wt% to about 5 wt% flavorant. Sweeteners useful in the present compositions include sucrose, fructose, aspartame, xylitol and saccharine.

The compositions may also contain active agents for treating adverse conditions of the teeth and surrounding tissue, e.g., periodontal and oral infections, periodontal lesions, dental caries or decay, and gingivitis. The active agent can be, for example, a nonsteroidal anti-inflammatory/analgesic, a steroidal anti-inflammatory agents, a local anesthetic agent, a bactericidal agent, an antibiotic, an antifungal agent, or a tooth desensitizing agent. See, e.g., U.S. Patent Publication Ns. US 2003/0152528 Al to Singh et al., published August 14, 2003, the disclosure of which is incorporated by reference herein.

The tooth whitening compositions of the invention can be applied to the teeth in any suitable manner, although it is preferred that the compositions be present as a flexible film that is applied across a row of teeth as a "tooth whitening strip."

To prevent release of whitening agent into mouth, a thin hydrophobic erodible backing layer may be used on the outer surface of tooth whitening strip which is comprised of a polymer composition that erodes in a moist environment at a same or slower rate than the hydrogel and is substantially impermeable for hydrogen peroxide. There are numerous materials that can be used for the backing member, and include, by way of example, and not limitation, polyolefins, polyesters, fluoropolymers and hydrophobic alkylacrylate polymers. Combinations, i.e., blends of any of these different polymers can also serve as backing member material.

In one embodiment, the hydrogel erodes in about 30 minutes to 24 hours after placement in a moist environment, and in another embodiment the hydrogel erodes about 30 minutes to 8 hours after placement. The erodible backing member, in one embodiment, erodes about 30 minutes to 24 hours after the hydrogel has eroded, while in another embodiment the backing erodes within about 3 hours after hydrogel has eroded. The erodible backing member material can be selected so as to erode at a slightly slower or approximately the same rate (e.g., when they both erode within about 24 hours), but is preferably selected so that it erodes at a slower rate than the hydrogel composition, when in use. In one embodiment, the erodible backing member erodes at least about 200% slower than the hydrogel, in another embodiment, the backing erodes at least about 100% slower, in a different embodiment the backing erodes at least about 50% slower, and in yet another embodiment the backing erodes at least about 5% slower than the hydrogel.

Because tooth whitening strip of present invention contains no backing film that is insoluble in saliva, it can be used as tooth whitening film for night application. Gradual solubility of the film in saliva obviates a danger of user's choking by the film during a sleep.

The tooth whitening compositions of the invention are used by removing the product from its package, typically a moisture-free sealed pouch, removing the release liner, and applying the adhesive layer to the teeth. The tooth whitening systems described herein can be provided in a variety of sizes, so that the composition can be applied to the entirety or any portion of a tooth, and to any number of teeth at one time. The system can be left in place for an extended period of time, typically in the range of about 10 minutes to 8 hours, preferably in the range of about 30 to 60 minutes. The system can be readily removed by peeling it away from the surface of the teeth.

The tooth whitening composition can be worn for an extended period of time, but will typically be worn for a predetermined period of time of from about 10 minutes to about 24 hours. A preferred time period is from about 10 minutes to about 1 hour, with about 30 minutes also being preferred.

A user can form the composition around the upper or lower teeth by applying normal manual pressure to the substrate with the tips of the fingers and thumbs, optionally by moistening the composition prior to application. Assuming the surface area of the average adult finger or thumb tip is approximately one square centimeter, the normal pressure generated by the finger and thumb tips is about 100,000 to about 150,000 Pascals (i.e., about 3 lbs. or 1.36 kg) per square centimeter. The pressure is typically applied to the composition by each finger and thumb tip for about one or two seconds. Once the pressure applied to the substrate by the tips of the fingers and thumbs is removed, the composition remains in the shape of, and adherent to, the surface of the teeth. When the user is ready to remove the tooth whitening composition, the composition can be removed simply by peeling it away from the surface of the teeth. If desired, the composition can be re-adhered for additional whitening time. Any residue left behind is minimal, and can be removed using conventional tooth cleansing methods.

The tooth whitening composition can also be applied as a non-solid composition, for example applied as a liquid or gel. For example, the user can extrude the composition from a tube onto a finger for application to the teeth, extrude the composition from a tube directly onto the teeth, apply the composition by means of a brush or other applicator, and so forth. After the evaporation of solvent, the composition dries to form a matrix-type polymer film on the surface of the teeth. In one embodiment of this liquid or gel film- former composition, the hydrogel contains sufficient water or other solvent to provide flowable property. In another embodiment of this composition, the polymer components of the liquid or gel composition are soluble in a water-ethanol mixture both at ambient temperature and at refrigeration temperatures of about 4°C, and are miscible upon solvent evaporation. In yet another embodiment of this liquid or gel film-former composition, the polymeric composition has a Lower Critical Solution Temperature of about 36°C in an ethanol-water mixture. The resulting film (after solvent evaporation) is preferably insoluble or slowly soluble in saliva at body temperature so as to provide lost lasting contact between the hydrogen peroxide and the dental enamel. Finally, the hydrogen peroxide should be stable both in the liquid or gel composition, as well as within polymer film upon drying.

It is to be understood that while the invention has been described in conjunction with specific embodiments thereof, the foregoing description 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, patent publications, journal articles, and other references cited herein are incorporated by reference in their entireties. EXPERIMENTAL:

The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make the tooth whitening formulations and systems of the invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.) but some experimental error and deviations should, of course, be allowed for. Unless indicated otherwise, parts are parts by weight, temperature is in degrees centigrade, and pressure is at or near atmospheric.

The following abbreviations and tradenames are used in the examples:

Advantage HC-37 vinyl caprolactam/vinyl pyrrolidone

/dimethylaminoethylmethacrylate copolymer, Ashland

Aquaflex SF-40 terpolymer of vinylcaprolactam (VCL), vinylpyrrolidone (VP) and dimethylaminopropyl methacrylamide

Ce(S0₄)₂ cerium sulfate

CP carbamide peroxide, Sigma - Aldrich

CPC carboxypropyl cellulose, Klucel^® Aqualon, USA

Eudragit L-100-55 metacrylic acid copolymer with ethyl acrylate (1: 1),

Rohm America Inc.

FFP film-forming polymer

HP 31 wt % aqueous solution of hydrogen peroxide

HPMCP hydroxypropyl methylcellulose phthalate, Shasun

Chemicals & Drugs (Japan)

GGaannttrreezz^®® SS 9977 maleic acid - methylvinyl ether copolymer (1:1), ISP Kollidon^® K-30 poly(N-vinyl pyrrolidone) M_w = 44,000 - 54,000 g/mol, BASF

Kollidon^® K-90 poly(N-vinyl pyrrolidone) M_w = 1,000,000 - 1,500,000 g/mol, BASF

Peroxydone^® K-90 PVP K-90 complex with hydrogen peroxide, ISP

Kollidon^® (Luviskol^®) VA64 vinyl pyrrolidone copolymer with 40 % of vinyl acetate, BASF

NCC noncovalent crosslinker

PEG-400 polyethylene glycol), M_w = 400 g/mol

PET polyethyleneterephtalate

PVA polyvinyl alcohol), 87 % hydrolysis, MW = 31,000

- 50,000, Sigma Aldrich

SF sol fraction, % TEC triethyl citrate, Morflex Inc.

Urea carbamide

G' elasticity modulus, MPa

G" loss modulus, MPa

Tg glass transition temperature, °C

tan δ loss tangent

a swell ratio

WH2O weight fraction of water in the sample under swelling during 10 min

Differential Scanning Calorimetry (DSC) was used to characterize the glass transition temperatures of prepared formulations. In the DSC apparatus the samples were first quench cooled with liquid nitrogen from ambient temperature to -150° C, subjected to isothermal annealing at this temperature and then heated up to 220° C at a rate of 20° C min^"1. The DSC heating traces were measured with a Mettler TA 4000 / DSC 30 thermoanalyzer, calibrated with indium and gallium. In the DSC measurements the samples of 5 - 15 mg in weight were sealed in standard aluminum pans supplied with pierced lids so that absorbed moisture could evaporate upon heating. An argon purge (50 mL min^'1) was used to avoid moisture condensation at the sensor. The glass transition temperature was measured as a middle point of heat capacity jump.

Elasticity shear modulus of the adhesives in the linear viscoelastic regime G' , loss modulus G" and tan δ were measured on a parallel plate Dynamical Mechanical Analyzer DMA 861 from Mettler Toledo, Switzerland. The amplitude of shear deformation was chosen to be in the linear regime of the elastic modulus G' over the whole range of temperatures. In dependence on PSA properties and temperature, this zone corresponded to a deformation less than 3 μηι. All measurements were performed at the temperature 37 °C and at 1 Hz frequency. The sample of swollen adhesive hydrogel upon immersion into citrate buffer solution with pH = 5.8 for 10 min was heated from ambient temperature with a rate of 3° C/min up to 37 °C and then annealed at this temperature for 10 min.

It is worthy of note that the value of glass transition temperature, measured with

DMA technique, is a function of deformation frequency. At the frequency of 1 Hz, this value can be of 40 ⁰ C higher than the true glass transitiontemperature, evaluated with DSC. For this reason, the former value can not be taken as a useful indicator of the PSA „ „

38

rigidity.

A circular samples of an adhesive film of 1 inch (2.54 cm) in diameter was die-cut with a punch. The samples were dried in an oven at 60 °C to constant weight. Then the samples were weighted and the masses were recorded (m₀, g). The first sample was then immersed into a jar containing 50 ml of citrate buffer with pH=5.6. In 10 min the swollen gel was removed and weighed (m_swio). Weight fraction of water in the sample under swelling during 10 min (swelling degree, WH₂O, g/g) was calculated using a ratio:

WH2O = (m_swl0-m_o)/ m_sw10

The jar with another sample was covered with a lid and stored in an incubator at 25 °C . Then the swollen sample was accurately taken from the jar and placed onto a release liner. Superficial excess moisture was accurately removed from the disk by careful blotting the sample with a Kimberly-Clark lab paper. Then the obtained swollen sample was weighed and the mass was recorded (m_sw, g). The swollen sample was deposited into an oven at 60 °C and dried to constant weight. The mass of the dry sample was recorded (m_dry, grams). The swell ratio (a, g/g) and sol fraction (SF, ) were calculated as follows:

a = m_sw / m_dr_y; SF (%) = 100 · ( m₀- m_dry) / m₀

Three replica samples were tested and average a and SF values were calculated. Quantitative analysis of peroxides in prepared tooth whitening compositions was underlied by chemical reaction:

2Ce⁴⁺ + H₂0₂→ 2Ce³⁺ +2H⁺ + 0₂

A sample of 50 - 100 mg in weight was immersed into a jar, following by addition of 15 ml ethanol, 1 ml distilled water and neutralization by 0.2 M KOH solution until pH = 8.5 - 9.0 was achieved. The mixture was stirred until the sample full dissolution. Then 5 ml of 5 M H₂S0₄ solution was added and titrated the mixture potentiometrically by 0.1 N solution of Ce(S0 )₂ using redoxy and calomel as indicator and reference electrodes, respectively, until potential jump of 500 - 900 mV was achieved. The content of hydrogen peroxide in the sample was calculated as:

V - N · MM - ι ,ι,ο,

( ) = ^■100

2w where V - titrant volume, ml, N - titrant normality, MM - peroxide molecular

MM_{II 0}

weight and w - sample weight, mg. — = 17 EXAMPLES 1 - 6

HYDROPHILIC PRESSURE SENSITIVE BIOADHESIVE COMPOSITIONS WITH TARGETED ADHESION TOWARDS TEETH

The compositions of hydrophilic bio-PSAs were prepared from the ingredients listed in Table 1.

) Reference sample

**) The composition refers to U.S. Patent Application No. 2003/0152528 by P. Singh, G.W. Cleary, S. Mudumba, M.M. Feldstein, and D.F. Bairamov. Bio-PSA film compositions of the invention containing the components listed in Table 1 were prepared using a casting from solution followed by drying method. Weighed amounts of FFP, NCC and plasticizer were dissolved in ethanol, using a high- torque, low speed mixing arm stirrer. Homogeneous solutions were cast onto Loparex Release Liner PET-RL-001U and dried at room temperature overnight. A uniform thickness of the films was obtained by using the BYK-Gardner film casting knife (AG- 4300 Series, Columbia, MD) as described earlier [Novikov M.B., Roos A., Creton C, Feldstein M.M., Dynamic mechanical and tensile properties of Poly(N-Vinyl Pyrrolidone)-Poly(ethylene Glycol) blends, Polymer, 2003, 44(12), 3559 - 3576]. Obtained films of 100 - 350 μπι in thickness were either transparent or translucent.

The bio-PSA compositions of the invention, exhibited by the Examples 1 - 3, contained a polyacid Eudragit L-100-55 as a FFP, whereas the Examples 4 - 6 were based on polybases PVP K-90, Kollidon K-30 and Kollidon VA-64. The composition on the Example 1 contained no polymeric NCC, while the compositions according Examples 2 - 6 where non-covalently crosslinked through the formation on interpolymer complexes. The reference composition of the Example 4 corresponds to the U.S. Patent Applications Nos. 2003/0152528, 2003/0235549, and 2004/0105834 by P. Singh, G.W. Cleary, M.M. Feldstein, D.F. Bairamov at al, which are treated as the prototypes of present invention. This composition contained PVP K-90 as FFP and Eudragit L-100-55 as polymeric NCC, which were taken in the ratio FFP : NCC = 4.9. In swollen state, the reference film of Example 4 demonstrates good adhesion to teeth and appreciable adhesion toward mucosal tissues in oral cavity. The composition is fastly dissolved, creating a sense of glue in a mouth. For this reason it needs in protecting backing film as is applied in tooth whitening formulations.

As is evident from the data presented in Table 1, a strong targeted adhesion of the hydrophilic bio-PSA films to teeth is provided as the ratio between concentrations of a FFP and polymer NCC in the compositions ranges from FFP : NCC = 2.3 (Example 5) to 1.6 (Example 6). The higher FFP : NCC = 4.9 value in Reference Examples 2 and 4 provides inadequate selective adhesion properties. The FFP : NCC ratio is a measure of noncovalent bond network density that determines cohesive strength, dissolution and swelling of the bio-PSA film. As the FFP : NCC→ 1, the noncovalent network becomes denser, solubility and swelling decrease and the cohesive strength rises. In turn, the noncovalent network density governs the blend rigidity, dictating the magnitudes of the G' modulus. As Example 1 has shown, the bio- PSA composition can be free of polymeric NCC. However, for proper selective adhesion the carboxyl groups of film-forming polyacid should form hydrogen bonds with complementary low molecular weight component exemplified by carbamide (urea). Due to very short distance between the carbamide aminogroups, urea is hardly capable of noncovalent crosslinking the polyacid macromolecules. Neverthess and in this case the bio-PSA material also consists of noncovalent acid-base complex.

Physical properties of materials depend on their molecular structure and are eventually controlled by the magnitute of their glass transition temperature (Tg). However, as follows from DSC data presented in Table 1, no unequivocal correlation is observed between the bio-PSA glass transition temperature and their selective adhesion toward teeth. The reason behind this apparent mismatch is that the Tg values in Table 1 relate to dry compositions, whereas selective tack to teeth is featured to swollen bio-PSA materials. In turn, the water absorbing capacity is dictated by the hydrophilicity and, consequently, chemical composition of the parent polymer components. PVP K-90, K-30 are more hydrophilic polymers than Kollidon VA-64 and Eudragit L- 100-55. In order to establish direct correlations we should take into our consideration the hydrophilicity of bio-PSA compositions.

With this purpose in Table 1 the amounts of moisture captured by the bio-PSA films upon their immersion into water for 10 minutes are presented. This time is sufficient for strong adhesive bonding of the films to tooth surface. The weight fraction of water absorbed by the film upon its immersion into aqueous citrate buffer solution for 10 minutes, w_H2oio_> corresponds approximately to the content of absorbed water in bioadhesive solid composition applied to teeth. As the w_swl0 is measured, the glass transition temperature of swollen in mouth bio-adhesive composition Tg can be evaluated using the Fox equation in the form:

where Wd_ry and T_gC)ry are wight fraction and glass transition temperature of the dry bioadhesive composition, and Tg_H2o is glass transition temperature of water. The value of the glass transition temperature of the water is a subject of debates [N. Giovambattista, C.A. Angell, F. Sciortino, H.E. Stanley, Glass transition temperature of water: A simulation study, Phys. Rev. Let. 2004, v. 93 No. 4 pp. 047801-1 - 047801-4]. We follow conventionally accepted magnitude, Tg_H2o = 136 K.

The values of glass transition temperatures of swollen bioadhesive compostions, Tg (sw.10 min), calculated using Equation (3), are presented in Table 1. As is seen from tabulated data, selective adhesion toward teeth is observed as the Tg (sw.10 min) value ranges between -44.1 to -126.0 °C, in accord with amount of captured water. Reference composition, exhibiting nonselective adhesion in oral cavity and described by Example 4, shows the Tg (sw.10 min) = -132.8 oC, only few degrees above the glass transition temperature of pure water.

As is known from the science of pressure sensitive adhesion, conventional hydrophobic PSAs possess the Tg values ranged between -10 and -113 °C [M.M. Feldstein, Molecular Nature of Pressure-Sensitive Adhesion, in: 1. Benedek, M.M. Feldstein (Editors), Fundamentals of Pressure Sensitivity (Handbook of Pressure - Sensitive Adhesives and Products), CRC - Taylor & Francis, Boca Raton, London, New York, 2009, Chapter 10, pp. 10-1 - 10-43]. Thus, targeted adhesion to teeth is a particular case of pressure sensitive adhesion exhibited by the swollen hydrogels in a mouth. When a dry, rigid nontacky hydrophilic polymer film is applied to teeth, the film swells and pressure sensitive character of adhesion appears as the result of Tg decrease due to a solid composition plasticization by absorbed water. The film plasticization by the water is accompanied by its softening and the decrease of elasticity modulus G' until the range established by the Dahlquist's criterion of tack is achieved. According to this empirical criterion, the G' values of PSAs at deformation frequency of 1 Hz are to be less than 0.3 MPa [Dahlquist C.A., Pressure-Sensitive Adhesives. in: Patrick R.L., Treatise on Adhesion and Adhesives, vol. 2, M. Dekker, N.Y., 219 - 260, 1969].

As DMA data presented in Table 1 have shown, the values of storage (elasticity) modulus G' of swollen bio-PSA lie in the range from to 0.054 to 0.39 MPa, while the reference composition (Example 4) possessing non-targeted adhesion to teeth and others mucosal tissues in oral cavity demonstrates abnormally low G' value of 0.0065 MPa. The G' value characterizes elastic material properties (the amount of mechanical energy stored by material in the course of deformation). The G' behavior is in good correlation with that of loss modulus G" which varies between 0.047 and 0.32 MPa for the PSAs with targeted adhesion to teeth. The G" value relates to the amount of mechanical energy dissipated by material during viscous flow. For the reference PSA with nonselective tooth adhesion the G" = 0.0035 MPa.

The G"IG' ratio, defined as the loss tangent, tan 5, is the balance of viscous/elastic behavior. Tan δ = 1 is a limiting value. Above this value the adhesive is generally considered as a viscoelastic fluid while below this value, the adhesive can be considered as a viscoelastic solid. Once tan δ > 1, the free volume dominates the cohesion energy. Conversely, if tan δ < 1, the contribution of cohesion energy overrides that of free volume.

As is seen from Table 1 data, all the PSAs with targeted adhesion to teeth demonstrate a perfect balance between viscous and elastic behaviors. For the majority of PSAs examined the elastic behavior dominates the contribution of viscous flow. For these PSAs the dissipation factor tan δ < 1, varying in very narrow range of magnitudes from 0.69 to 0.94. A single PSA showing domination of viscous flow over elasticity is the PSA described in Example 6 (tan δ = 1.11). The reference PSA in Example 4 with non- targeted tooth adhesion exhibits abnormally strong contribution of elastic behavior (tan δ = 0.54) notwithstanding the fact that the hydrogel contains 95 % of absorbed water.

Generalizing the data in Table 1, we can conclude that strong adhesion to teeth, coupled with the lack of adhesion to soft mucosal tissues in oral cavity, occurs if following characteristics of the swollen hydrophilic composite material are observed: Tg is between -40 and -126 ⁰ C, G' < 0.4 MPa and tan δ in the range from 0.69 to 1.11. These values can be featured for hydrophilic polymers capable of swelling in water and possessing the swell ratio in the range from 2 to 15. The content of sol fraction has a little or no effect on the selective adhesion behavior. The bioadhesive compositions with high sol fraction can be especially useful in night-time usable tooth-whitening products, which could self-erode after the active agent has been released or the desired therapeutic or cosmetic effect has been achieved, owing to gradual polymer film dissolution in saliva. All these factors should be provided in combination. If a value of a some single factor departs from this rule, selective adhesion vanishes.

In Interpol ymer and polymer - oligomer FFP - NCC complexes, the foregoing physical properties of the bioadhesive compositions are realized if the FFP : NCC ratio varies from 1 to 3.

EXAMPLE 7 APPLICATION OF HYDROPHILIC PRESSURE SENSITIVE

BIOADHESIVE FILM COMPOSITIONS WITH TARGETED ADHESION TOWARDS TEETH IN COSMETOLOGY

Being immersed into liquid water or placed in mouth, the bio-PSA films demonstrate a phase separation. As a result, the swollen films become snow-white and closely adjoin to the teeth, accepting their relief. Due to strong adhesion to teeth and the lack of adhesion to tongue, gums, palate, lips and soft buccal tissues, the films provide freedom of speaking and demonstrate a sunny smile. Owing to this valuable quality, the bio-PSA films containing no tooth-care ingredients can be useful in cosmetology for temporary decoration of user teeth, in particular during interview, public performances, telecasts, etc.

If desired, a translucent composition can be also provided, and is worn without being obtrusive or noticeable to others. The system can be designed without an active ingredient and finds utility as a protective dressing for tooth surface, e.g. canker sore, cold sore, etc or as a wound dressing.

EXAMPLE 8

TOOTH WHITENING FILM COMPOSITION BASED ON POLYACID BLEND WITH CARBAMIDE PEROXIDE

One embodiment of a film composition for tooth whitening was prepared from the following ingredients using a casting - drying process:

Eudragit L-100-55 57.4 wt. %

CP 22.6 wt. %

TEC 20.0 wt. %

Weighed amounts of CP (0.8 g) and TEC (0.7088 g) were dissolved in 5 and 2 ml of ethanol, correspondingly, using magnetic stirrer. Obtained solutions were placed into a glass jar along with 13 ml of ethanol. Eudragit L-100-55 was added slowly (within 2 - 5 min) under vigorous stirring conditions. The composition was mixed in a Cole-Parmer high-torque low-speed lab mixer supplied with Teflon coated impeller (2 inches in diameter).

Obtained films of 50 μπι in thickness were translucent and flexible. The films manifested no adhesion to dry finger skin, but strong adhesion to teeth upon contact under slight pressure by finger. The films exhibited wear time above 1 hr and no adhesion towards oral mucosa. However, quantitative analysis for HP demonstrated zero content of active peroxide, implying that the hydrogen peroxide was decomposed in the course of sample preparation.

This result is consistent with earlier reported research data by J.A. Dobado, J. Molina, D. Portal, Theoretical Study on the Urea-Hydrogen Peroxide 1:1 Complexes, J. Phys. Chem. A 1998, 102, 778-784, which demonstrated the HP decomposition in the presence of weak organic acid's carboxyl groups in solutions. At the same time, carboxyl groups of Eudragit L-100-55 polyacid provide strong selective adhesion of the film composition to tooth surface and a lack of adhesion toward mucosa, reached with polyanion. This conclusion outlines a fundamental problem of the HP stabilization in the presence of polyacids. Resolutions of this problem are described in Examples 9 - 17.

EXAMPLES 9 - 16

HYDROPHILIC TOOTH CARE PRESSURE SENSITIVE BIOADHESIVE

FILMS

According to the approach of present invention, to prevent the HP decomposition in the course of preparation of tooth whitening bioadhesive films using casting - drying method, the carboxyl groups of a polyacid should be blocked by their hydrogen bonding with complementary functional groups of polymer NCC, oligomer or low molecular weight agent.

The compositions of hydrophilic bio-PSA films for tooth whitening were prepared from the ingredients listed in Table 2.

As the data in Table 2 have shown, tooth whitening bioadhesive films outlined by Examples 9 and 10 contain polyacid Eudragit L-100-55 as FFP. As tooth whitening agent the film corresponding to Example 9 includes CP. The CP interaction with polyacid in solution leads to partial decomposition of HP. As a result, at the load of 10 wt %, the content of hydrogen peroxide in the film is about 2.4 wt %. In order to increase the HP concentration in dry film, in Example 10 the polyacid was first mixed with urea and liquid HP was added to the mixture. This results in higher HP concentration in bioadhesive film (5.5 wt. %). The uncrosslinked tooth whitening compositions described by Examples 9 and 10 refer to bioadhesive film described in Example 2. They possess excellent adhesion toward teeth and no mucoadhesion. Splendid adhesion defines long wearing the whitening films on teeth.

Tooth whitening films on Examples 11 - 16 contain polybase as FFP. The film composition disclosed by Example 11 include high molecular weight PVP complex with HP (Peroxydone K-90) as FFP and the source of whitening agent. The PVP is noncovalently crosslinked through comparatively short chains of PEG-400, bearing complementary hydroxyl groups on both ends of oligomer molecule. In this way, the PEG-400 simultaneously behaves as NCC and plasticizer of PVP. Because both components of the composition are water soluble, the bioadhesive film dissolves in saliva over 10 - 15 minutes.

Formulations 12 - 15 utilize the mixture of two polybases, PVP (Kollidon K-30) and vinyl pyrrolidone copolymer with 40 mol % of vinyl acetate (Kollidon VA64) as FFP. The content of Kollidon VA 64 in blends with PVP increases from 31.8 (Example 12) to 40.2 wt % (Example 15). In contrast to PVP, the Kollidon VA64 is much less soluble in water. The bio-PSA film on Example 16 contains pure Kollidon VA64 as the FFP and no PVP K-30. The FFP:NCC ratio varies from 3.0 to 1.9. All the films demonstrate excellent adhesion to teeth and no mucoadhesion, defining the time of tooth whitening film wearing that exceeds 1 hour (at film thickness of 100 - 150 μπι).

Compositions 12 and 13 contain carbamide peroxide as tooth whitening agent, while all other films use 31 wt % aqueous solution of hydrogen peroxide. In composition 13 the carbamide peroxide is incorporated into film along with HP. All the formulations provide sufficient stability of the whitening agent in the process of film preparastion by casting - drying method. The procedure of film production is described above in Examples 1 - 6. EXAMPLES 17 - 24

TOOTH WHITENING BIOADHESIVE COMPOSITIONS BASED ON NONCOVALENT COMPLEXES OF HYDROHILIC FUNCTIONAL POLYMERS

Examples 9 - 16 employ model polymers - Eudragit L-100-55 polyacid, and the vinyl pyrrolidone - based homo- and copolymers, polybases Kollidon K-30, K-90 and Kollidone VA64 - as FFP and NCC in tooth whitening compositions with selective adhesion to teeth. Nevertheless these hydrophilic polymers by no means exhaust a long list of components suitable for application in the bioadhesive platforms for tooth whitening strips. Some other eligible polymers are described in Examples 17 - 24.

Using casting - drying method described in Examples 1 - 6, the hydrophilic bio-

PSA compositions with peroxides were prepared from the complementary functional polymers listed in Table 3.

The compositions corresponding to the Examples 17 - 19 involve polybase Kollidon VA64 as FFP and carboxyl- or hydroxyl group containing cellulose derivatives as NCC. The tooth whitening compositions outlined by the Examples 19 and 20 employ the mixtures of the carboxyl group containing polymeric NCC, Eudragit L-100-55, with the polymers bearing hydroxyl groups in thir recurring units, hydroxypropyl cellulose (HPC) and polyvinyl alcohol) (PVA). The carboxyl groups form stronger hydrogen bonds than the hydroxyl groups. In this way, minor NCC (CPC or PVA) behave as compatibilizers between the NCC and FFP, facilitating the formation of more ductile interpolymer network.

As follows from Examples 4 and 5, reference U.S. Patent Applications Nos.

2003/0152528, 2003/0235549, 2004/0105834, 2006/0171906 by P. Singh, G.W. Cleary, M.M. Feldstein, D.F. Bairamov at al., and from research paper by P.E. Kireeva, M.B. Novikov, P. Singh, G.W. Cleary, M.M. Feldstein, Tensile properties and adhesion of water absorbing hydrogels based on triple poly (N -vinyl pyrrolidone) I poly(ethylene glycol) I poly (methacry lie acid - co - ethylacrylate) blends, J. Adhesion Sci. Technol., vol. 21 No. 7, 2007, pp. 531 - 557, the stoichiomeric PVP network complex with PEG- 400, crosslinked noncovalently by comparatively small amounts of Eudragit L-100-55, is very successful bioadhesive platform for tooth whitening products. As Examples 4 and 5 have shown, PVP is too hygroscopic polymer, and its compositions dissolve in saliva very quickly, creating a sense of glue in mouth. In contrast, Poly(N-vinyl caprolactam) (PVCL) belongs to the same class of polyvinyl amides as the PVP, but differs from the PVP by lower hydrophilicity and less solubility in aqueous media. As Example 21 demonstrates, a ternary PVCL-PEG-Eudragit L-100-55 complex provides successful combination of properties and serves as useful bio-adhesive platform for tooth whitening.

Gantrez S 97 is a maleic acid copolymer with methylvinyl ether. As Example 22 indicates in comparison with Example 10, its hydrogen bonded complex with urea exhibits selective adhesion to the surface of teeth and provides the stability of absorbed hydrogen peroxide molecules. Thus, the polyacids of different chemical structure can be used in bio-adhesive platforms for tooth whitening.

Examples 23 and 24 illustrate bioadhesive tooth whitening compositions based on vinyl pyrrolidone - vinyl caprolactam - acrylic tercopolymer polybases, Advantage HC- 37 and Aquaflex SF-40, both available from Ashland. The third copolymer in the Advantage HC-37 is dimethylaminoethyl methacrylate, whereas the Aquaflex SF-40 contains dimethylaminopropyl methacrylamide. All the compositions provide perfect adhesion to teeth, no mucoadhesion, and hydrogen peroxide stability.

Physical properties of the tooth whitening compositions in Examples 8 - 24, responsibe for targeted adhesion to teeth, are as follow:

the glass transition temperature of swollen hydrogel, measured in 10 min upon its immersion into aqueous medium - from -10 to -130 °C;

the elasticity modulus in swollen state G' < 0.45 MPa;

loss tangent in swollen state - from 0.60 to 1.20

weight fraction of water in the sample under swelling during 10 min - from 0.1 to

0.7;

swell ratio - between 1 and 15.

EXAMPLE 25

TOOTH WHITENING COMPOSITIONS IN LIQUID OR GEL FORM

The liquid and hydrogel compositions relating to solid tooth whitening formulations, described in Examples 8 - 24, can be also applied to teeth surface in the form of relevant casting solutions in ethanol. The method of liquid composition prepararion is illustrated by the following typical procedure.

A liquid composition for tooth whitening was prepared by mixing the following components with magnetic stirrer:

Ethyl alcohol 15 ml

Hydrogen peroxide (30 % aqueous solution) 1.

Eudragit L-100-55 3.75 g

Carbamide peroxide 0.92 g

TEC 0.58 g

Liquid tooth whitening product is clear gel applied with a small brush or cotton bud directly to the surface of teeth. Put the gel straight onto exposed smiling teeth and dry for 30 s. Instructions generally call for twice a day application for 14 days. Initial results are seen in a few days and final results are sustained for about four months.

EXAMPLE 26

COATING TOOTH WHITENING STRIP WITH BIOERODIBLE PROTECTIVE PEROXIDE IMPERMEABLE LAYER

To prevent hydrogen peroxide release to the mouth from the strip applied to the teeth, opposite side of the strip, faced to tongue, should be covered by a thin (5 - 10 μηι) protective hydrophobic layer, impermeable for water and hydrogen peroxide. As materials for the protective layer, waxes I and II (Microcrystalline Paraffin 180/185 and Microcrystalline Paraffin 140/145) can be used, supplied by Wacker.

The strip coating with wax layer can be provided by casting-drying from hexane solution or from melt, using a paper applicator, by spraying one side of the strip with wax solution, and by applying the wax with small brush.

EXAMPLE 27

TOOTH WHITENING STRIPS DESIGNED FOR APPLICATION TO UPPER AND LOWER TEETH

In oral cavity saliva is mainly accumulated at lower row of teeth. For this reason the strips applied to lower teeth absorb much more moisture than the strips attached to upper teeth. In this connection the tooth whitening compositions designed for application to lower teeth should posess higher creep resistance to fix the strip in situ.

To enhance creep resistance of hydrated tooth whitening composition, two approaches can be used. The first approach consists in the increase of moisture absorbing capacity of the composition and represents incoropration of water absorbents. Suitable absorbents of moisture can be either in the form of particles, mixed with the composition, or in the form of hydrophilic woven and nonwoven materials, impregnated by the adhesive. Particle absorbents include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesium silicate, starch, calcium sulfate, calcium stearate, calcium phosphate, clays such as laponite, polyacrylamide known under trademark Water Lock^® Superabsorbent Polymer, available from SNI Solutions. Appropriate woven and nonwoven fabrics can be separated from the class of paper and cotton materials.

Alternative approach to enhance creep resistance of tooth-whitening composition relates to the increase of noncovalent crosslinking density. With this purpose the FFP'.NCC concentration ratio should be decreased, tending to unity. The increase in creep resistance can be achieved by mixing the adhesive composition with inert fillers, i,e. polyurethane polyether amide copolymers, polyesters and polyester copolymers, nylon and rayon. A preferred filler is colloidal silica, e.g. Cab-O-Sil^® (Cabot Corporation, Boston Mass).

Claims

1. Hydrophilic pressure sensitive bioadhesive comprising a non-covalent complex of a film-forming polymer at least with one of following complementary components: crosslinking polymer agent,

crosslinking oligomer agent,

low molecular weight substance,

or with a blend at least with two of listed components,

where the film-forming polymer and the crosslinking polymer agent are selected from the hydrophilic polymers,

therewith the bio-adhesive components are taken in the amounts providing the preparation of the complex possessing an adhesion to the surface of teeth and the lack of adhesion toward other tissues in oral cavity with following charactristics:

the glass transition temperature in swollen state from -10 to -130 °C,

the elasticity modulus G' in swollen state less than 0.45 MPa,

the loss tangent in swollen state from 0.60 to 1.20,

the swelling degree at immersion into aqueous medium for 10 minutes from 0.1 to

0.7,

the swell ratio from 1 to 15.

2. The bioadhesive of claim 1 that additionally contains at least one plasticizer.

3. The bioadhesive of claim 1, wherein the film-forming polymer and the crosslinking polymer agent are taken in the weight ratios from 3:1 to 1:1.

4. The bioadhesive of claim 1, wherein the film-forming hydrophilic polymer is present in the concentration 20 - 90 wt. % in blend, preferably 30 - 80 wt. %, and the most preferably 40 - 60 wt. %.

5. The bioadhesive of claim 1, the glass transition temperature of which is measured with the differential scanning calorymetry at heating with a rate of 20 °/min.

6. The bioadhesive of claim 1, wherein the film-forming polymer is a polyacid, and the noncovalent crosslinking polymer agent is a polybase.

7. The bioadhesive of claim 1, wherein the film-forming polymer is a polybase, and the noncovalent crosslinking polymer agent is a polyacid.

8. The bioadhesive of claims 6 or 7, wherein the polyacid is selected from the polyacrylic acid, polymethacrylic acid, polymaleic acid, polyvinyl alcohol, polyvinyl phenol, cellulose derivatives containing carboxyl or hydroxyl groups, their blends or the copolymers of corresponding monomers with each other or with other monomers, and the polybase is selected from the poly(N-vinyl lactams), poly(N-vinyl amides), poly(N- alkylacrylamides), polyvinylamines, relevant copolymers and other polymers containing aminogroups, polyurethanes, polypeptides, their copolymers, proteins, chitosans, as well as from the blends of the stated polybases.

9. The bioadhesive of claim 1, wherein the film-forming polymer is a methacrylic acid copolymer with alkylacrylates or metacrylates, or is a maleic acid copolymer with alkyl ether of vinyl alchohol, or is a carboxyl-containing cellulose derivative.

10. The bioadhesive of claim 1, wherein the film-forming polymer is selected from the group of poly(N-vinyl pyrrolidone), poly(N-vinyl valerolactam), poly(N-vinyl caprolactam) copolymers and blends thereof.

11. The bioadhesive of claim 1, wherein the film-forming polymer is selected from poly(dialkyl aminoalkyl acrylates), poly(dialkyl aminoalkyl methacrylates), poly(N,N-dialkyl acrylamides), poly(trimethylammonioethyl methacrylate), poly(N-vinyl lactams), copolymers thereof, and combinations of any of the foregoing.

12. The bioadhesive of claim 1, wherein the film-forming polymer is chitosan.

13. The bioadhesive of claim 1, wherein the film-forming polymer has a number average molecular weight in the range of approximately 100,000 to 2,000,000 g/mol, preferably from 500,000 to 1.500,000 g/mol.

14. The bioadhesive of claim 1, wherein the crosslinking polymer agent is chitosan.

15. The bioadhesive of claim 1, wherein the crosslinking agent includes one or few complementary polymers and/or oligomers which non-covalently crosslink the film- forming polymer into three-dimensional, cohesively strong, network supramolecular structure.

16. The bioadhesive of claim 1, wherein the crosslinking agent is a complementary oligomer containing reactive groups at the ends of short chain, therewith the film-forming polymer is crosslinked by the complementary oligomer through hydrogen bonding.

17. The bioadhesive of claim 16, wherein the complementary oligomer containing reactive groups at the ends of short chain has the molecular weight in the range from about 45 to 800 g/mol, preferably from about 300 to 600 g/mol.

18. The bioadhesive of claim 16, wherein the complementary oligomer is selected from the group consisting of polyalcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, carboxyl-teminated polyalkylene glycols, amino-terminated polyalkylene glycols, ether alcohols, alkane diols and carbonic diacids.

19. The bioadhesive of claim 18, wherein the complementary oligomer is selected from the group consisting of polyalkylene glycols and carboxyl-terminated polyalkylene glycols.

20. The bioadhesive of claim 1, wherein the complementary oligomer is polyethylene glycol, preferably the polyethylene glycol 400.

21. The bioadhesive of claim 2, wherein the polyethylene glycol is used as a plasticizer, preferably the polyethylene glycol 400.

22. The bioadhesive of claim 2, wherein the plasticizer is a low molecular weight plasticizer.

23. The bioadhesive of claim 22, wherein the low molecular weight plasticizer is selected from the group consisting of dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates, mixed alkyl-aryl phthalates, alkyl phosphates, aryl phosphates, alkyl citrates, alkyl citrate esters, citrate esters, alkyl adipates, dialkyl tartrates, dialkyl sebacates, dialkyl succinates, alkyl glycolates, alkyl glycerolates, glycol esters, glycerol esters, and mixtures thereof.

24. The bioadhesive of claim 22, wherein the low molecular weight plasticizer is selected from the group consisting of dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di(2-ethylhexyl)phthalate, di-isopropyl phthalate, diamyl phthalate, dicapryl phthalate, tributyl phosphate, trioctyl phosphate, tricresyl phosphate, triphenyl phosphate, trimethyl citrate, triethyl citrate, tributyl citrate, acetyl triethyl citrate, trihexyl citrate, dioctyl adipate, diethyl adipate, di(2-methylethyl)adipate, dihexyl adipate, diethyl tartrate, dibutyl tartrate, diethyl sebacate, dipropyl sebacate, dinonyl sebacate, diethyl succinate, dibutyl succinate, glycerol diacetate, glycerol triacetate, glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate, triethylene glycol dipropionate, and mixtures thereof.

25. The bioadhesive of claim 1, wherein the content of components provides production of the composition in the form of transparent or translucent film which turns white once attached to teeth.

26. The bioadhesive of claim 1, wherein the low molecular weight substance is urea.

27. Tooth care composition including hydrophilic pressure sensitive bioadhesive of any of claims 1 - 25 and one or more active agents.

28. The composition of claim 27, wherein the active agents are the substances and blends thereof which are selected from the group: tooth whitening agents, anticalculus agents, floride ion sources, antimicrobial agents, anti-inflammatory agents, nutrients, antioxidants, H2 antagonists, desensitizing agents, antiviral agents, antimycotic agents, coloring agents, chelating agents, surfactants, pigments and the mixtures thereof.

29. The composition of claim 28, wherein the tooth whitening agent is selected from the group consisting of peroxides, metal chlorites, percarbonates, peroxyacids, and combinations thereof.

30. The composition of claim 29, wherein the peroxide is selected from the group consisting of hydrogen peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof.

31. The composition of claim 29, wherein the peroxide is an organic peroxide.

32. The composition of claim 31, wherein the organic peroxide is selected from the group consisting of dialkyl peroxides, diacyl peroxides, peresters, perdicarbonates, ketone peroxides, and hydroperoxides.

33. The composition of claim 32, wherein the dialkyl peroxide is f-butyl peroxide or 2,2 bis(t-butylperoxy)propane.

34. The composition of claim 32, wherein the diacyl peroxide is benzoyl peroxide or acetone peroxide.

35. The composition of claim 32, wherein the perester is i-butyl perbenzoate or t- butyl per-2-ethylhexanoate.

36. The composition of claim 32, wherein the perdicarbonate is dicetyl peroxy dicarbonate or dicyclohexyl peroxy dicarbonate.

37. The composition of claim 32, wherein the ketone peroxide is cyclohexanone peroxide or methylethylketone peroxide.

38. The composition of claim 32, wherein the hydroperoxide is cumene hydroperoxide or tert-butyl hydroperoxide.

39. The composition of claim 28, wherein the tooth whitening agent is a metal chlorite selected from the group consisting of calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, potassium chlorite, hypochlorite, and chlorine dioxide.

40. The composition of claim 28, containing two or more different tooth whitening agents.

41. The composition of claim 28, which comprises 0.1 - 60 wt % of tooth whitening agents.

42. The composition of claim 40, comprising an admixture of a first tooth whitening agent that is inert in a dry environment but activated upon contact with moisture to release hydrogen peroxide gradually and produce an alkaline pH; as a second tooth whitening agent a substance is employed that is inert in a dry environment but activated upon contact with aqueous base and releases as an example the hydrogen peroxide rapidly.

43. The composition of claim 40, wherein the first tooth whitening agent is carbamide peroxide.

44. The composition of claim 40, wherein the second tooth whitening agent is sodium percarbonate.

45. The composition of claim 28, wherein the low molecular weight substance stabilizes the whitening agent.

46. The composition of claim 28, wherein the low molecular weight substance stabilizing the tooth whitening agent is urea.

47. The composition of claim 28, wherein the film-forming polymer is a polyacid, the non-covalent crosslinking agent and plasticizer is polyethylene glycol, the tooth whitening agent is selected from peroxides, the low molecular weight substance is urea, and therewith the peroxides are incorporated into the composition following the mixing of the film-forming polymer with the non-covalent crosslinking agent and the urea.

48. The composition of claim 27, further comprising at least one additive selected from the group consisting of fillers, preservatives, pH regulators, softeners, thickeners, colorants, pigments, dyes, refractive particles, flavorants, sweeteners, stabilizers, toughening agents, detackifiers, and permeation enhancers.

49. The composition of claim 48, wherein the flavorant is selected from the group consisting of wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils and oleoresins, and combinations thereof.

50. The composition of claim 48, wherein the sweetener is selected from the group consisting of sucrose, fructose, aspartame, xylitol and saccharine.

51. The composition of claim 27, wherein the component content provides the composition in the form of flexible film.

52. The composition of claim 27, further containing a volatile solvent, therewith the component content ensures the composition in the form of transparent or translucent solution or gel.

53. The composition of claim 51, further containing water absorbing filler.

54. The composition of claim 53, wherein the water absorbing filler represents solid paricles, woven or nonwoven material.

55. The composition of claim 51, wherein the film contains an outer polymer coating which is impermeable for hydrogen peroxide and water.

56. The composition of claim 51, wherein the film represents a strip insoluble in saliva, of 50 to 500 μπι, preferably of 100 to 350 μπι in thickness.

57. The composition of claim 51, wherein the component content gives the film, dissolving or eroding in saliva within 30 minutes to 24 hours, preferably from 30 minutes to 8 hours.