KR20070017470A - Hydrogel Compositions with an Erodible Backing Member - Google Patents

Abstract

A composition comprising a water swellable water insoluble polymer and a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen or electrostatic bonding to a hydrophilic polymer is provided. The composition also includes a backing member. It may include active ingredients such as whitening agents. The composition can be used as an oral dressing, for example as a tooth whitening composition applied to teeth in need of whitening. The composition can be designed to be completely eroded by being removed or placed in place when the degree of whitening is achieved. In certain embodiments, the composition is translucent. Also disclosed are methods of making and using the composition.

Erodible backing member, hydrogel composition, tooth whitening agent, wound dressing, water swellable water insoluble polymer

Description

Hydrogel Compositions with Erodable Backing Member

The present invention relates generally to hydrogel compositions. More specifically, the present invention relates to hydrogel compositions useful as wound dressings and useful for administering various active agents to mucosal tissues such as mouths, including tooth whitening agents.

Discoloration of teeth occurs widely in society and is estimated to occur in two out of three adults. Tooth discoloration is considered an aesthetic defect or flaw and can negatively affect the lives of individuals with tooth discoloration by causing self-consciousness and even laughing. Tooth discoloration can be particularly painful or troublesome for situations and occupations where clean, white teeth are important.

The tooth consists of an inner dentin layer and a slightly porous outer hard enamel layer. The outer layer is the layer that protects the teeth. The original color of the teeth is opaque to translucent white or slightly off-white. Tooth pigmentation occurs as a result of exposure of compounds such as tannins and other polyphenolic compounds to the teeth. These compounds are trapped or bound in the protein layer on the tooth surface and can penetrate enamel and even dentin. Occasionally, pigmentation may occur from a source in the tooth, such as tetracycline, which may deposit on the tooth when administered to an individual as a child.

Surface pigmentation can generally be removed by mechanical tooth cleaning. However, discolored enamels or dentin are not treated by the mechanical methods of tooth cleaning and chemical methods that can penetrate into the tooth structure, which are required to remove pigmentation. The most effective treatment of tooth pigmentation is a composition containing an oxidizing agent, such as hydrogen peroxide, which can react with the chromogen molecules responsible for pigmentation and render them colorless or water soluble or colorless and water soluble.

Accordingly, tooth whitening compositions generally include gels, pastes, or liquids, including cream toothpastes that are mechanically agitated at two categories, namely (1) the surface of the colored tooth to affect removal of the tooth through abrasive erosion of the surface pigmentation, and (2) After the preparation is removed by a chemical process during contact with the colored tooth surface for a certain period of time, it is divided into gel, paste, or liquid in which the tooth bleaching effect is achieved. In some cases, cochemical processes, which may be by oxidation or enzymes, supplement the mechanical process.

Some dental compositions, such as dentrifices, cream toothpastes, gels and powders, contain active oxygen or hydrogen peroxide that releases bleach. Such bleaching agents include complex compounds containing peroxides, percarbonates and perborates or hydrogen peroxides of alkali and alkaline earth metals. In addition, peroxide salts of alkali or alkaline earth metals are known to be useful for whitening teeth.

Among the many peroxides available for the preparation of tooth whitening compositions, hydrogen peroxide (and adducts or associated complexes thereof, such as carbamide peroxide and sodium percarbonate) are used almost exclusively. The specific nature of the interaction of hydrogen peroxide with tooth chromogen is unknown, but the chemical properties of hydrogen peroxide are well known. It is believed that hydrogen peroxide destroys tooth chromogens by oxidizing the unsaturated carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds found in colored molecules, thereby making them colorless or soluble.

The class of compounds involved, peroxy acids, are mainly used in laundry detergents by whitening clothes effectively because of their stability in solution and their specific binding capacity to certain types of colored molecules. Many stable solid peroxy acids are used, including magnesium salts of diperoxydodecanoic acid and monoperoxyphthalic acid. Other peroxy acids, such as peroxyacetic acid, are available in solutions containing an equilibrium distribution of acetic acid, hydrogen peroxide, peroxyacetic acid and water. Alternatively, peroxide donors such as sodium perborate or sodium percarbonate are formulated with a peroxy acid precursor. Upon contact with water, the peroxide donor releases hydrogen peroxide which subsequently reacts with the peroxy acid precursor to form the actual peroxy acid. Examples of peroxy acids produced in situ include peroxyacetic acid (from hydrogen peroxide and tetraacetylethylenediamine) and peroxynonanoic acid (from hydrogen peroxide and nonanoyloxybenzene sulfonate).

Peroxy acids are also used in oral care compositions that whiten pigmented teeth. US Pat. No. 5,279,816 to Church et al. Describes a tooth whitening method comprising the application of a peroxyacetic acid containing composition having an acidic pH. European patent 545,594 Al (Church et al.) Describes the use of peroxyacetic acid in the preparation of compositions for tooth whitening. Peroxyacetic acid can be present in the composition or, alternatively, can be produced in situ by combining a peroxide source with a peroxyacetic acid precursor during use. For example, US Pat. No. 5,302,375 to Viscio describes compositions that produce peroxyacetic acid in the vehicle in situ by combining water, acetylsalicylic acid and water soluble alkali metal percarbonate.

The most commonly used dental whitening agents are carbamide peroxide (CO (NH ₂ ) ₂ H ₂ 0 ₂ ), also called urea hydrogen peroxide, hydrogen peroxide carbamide and perhydrol-urea. Carbamide peroxide has been used for oral disinfectants by dental clinicians for decades, and tooth bleaching has been observed as a side effect of prolonged contact. Commercially available (over-the-counter) composition of 10% Carbamide peroxide has a low viscosity, which must be held in a tray or similar container in order to provide contact with the teeth is also the composition of glycidyl-oxide ^{® (®} GLY-OXIDE) ( Marion as provided below to see grease soil (Marion Laboratories)) and proxy gel ^{® (®} PROXIGEL) (lead-and kanrik (Reed and Carnrick) service) can be used. Bleaching gel that can be held for extended periods of time situated in a comfortable custom teeth tray is a trademark Opal's Lessons ^® (OPALESCENCE ^®) Ultra Dent Products, Inc. (Ultradent Products, Inc., United States, Utah, South Jordan, written materials) are available .

In order for these compositions to stay in place, the compositions must be viscous liquids or gels. In addition, when the dental tray is used, the tray must be adapted to fit comfortably and without pressure or irritation on a person's teeth or gums. Such whitening compositions must be formulated to be sufficiently adhesive and viscous to withstand dilution by saliva.

In one method of whitening an individual's teeth, the dental practitioner assembles a custom tooth bleach tray for the patient from a pattern of denture made from the patient's dentition for the patient, administered in the bleach tray and about 2 depending on the severity of the tooth pigmentation The use of an oxidized gel will be prescribed that will be worn intermittently for a week to about 6 months. These oxidizing compositions, typically packaged in small plastic syringes or tubes, are administered directly by the patient into a custom tooth bleach tray that is held in place in the mouth for more than about 60 minutes, sometimes 8 to 12 hours of contact time. The slow bleaching rate is largely due to the very nature of the formulations developed to maintain the stability of the oxidizing composition.

For example, US Pat. No. 6,368,576 to Jensen describes tooth whitening compositions, preferably used with trays, such that the composition is located and held close to the tooth surface of the individual to be treated. These compositions are described as adhesive matrix materials formed by combining a sufficient amount of tackifier such as carboxypolymethylene with a solvent such as glycerin, polyethylene glycol or water.

In another example, US Pat. No. 5,718,886 (Pellico) describes tooth whitening compositions in the form of gel compositions containing carbamide peroxide dispersed in anhydrous gelatin carriers including polyols, thickeners and xanthan gum.

Yet another example contains carbamide peroxide (0.3-60%), xylitol (0.5-50%), potassium salt (0.001-10%) and fluorine salt (0.15-3%), with suitable gelling agents Is described in US Pat. No. 6,419,905 (Hernandez), which describes the use of a composition formulated as a gel containing 0.5 to 6% by weight.

Tooth whitening compositions for attachment to teeth are described in US Pat. No. 5,989,569 and 6,045,811 to Dirksing. According to these patents, the gel is 30-85% glycerin or polyethylene glycol, 10-22% urea / hydrogen peroxide complex, 0-12% carboxypolymethylene, 0-1% sodium hydroxide, 0-100% triethanol Amine (TEA), 0-40% water, 0-1% fragrance, 0-15% sodium citrate, and 0-5% ethylenediaminetetraacetic acid. Preferred gels according to the Dirksing have a viscosity of 200 to 1,000,000 cps at low shear rates (less than 1 1 / sec) and are sufficiently adhesive that no tray is required.

Currently available tooth bleaching compositions have a serious disadvantage of causing tooth sensitivity in at least 50% of patients. Because of the presence of glycerin, propylene glycol and polyethylene glycol in these compositions, tooth sensitivity can result from the movement of fluid through dentin tubules that are sensed by nerve endings in the tooth. This can change the degree of tooth sensitivity after teeth are exposed to heat, cold, excessively sweet substances, and other causative agents.

Prolonged tooth exposure to the currently implemented bleaching compositions causes many side effects in addition to side effects on tooth sensitivity. These side effects include calcium leaching from the enamel layer below pH 5.5, risk of damage to pulp tissue due to infiltration of enamel and dentin intact with bleach, dilution of the bleaching composition by saliva and leaching from the dental tray. Then, it is ingested by a user.

Some oxidizing compositions (typically having relatively high concentrations of oxidant) are applied directly to the patient's tooth surface at the dentist under the supervision of a dentist or dental hygienist. In theory, this tooth whitening method yields faster results and better overall patient satisfaction. However, because of the high concentrations of oxidants contained in these, called “in-office” compositions, they can be dangerous to patients, practitioners, and the like if not handled with care. The patient's soft tissues (gingiva, lips, and other mucosal surfaces) must first be isolated from potential exposure to active oxidants using perforated rubber sheets (known as rubber dams) so that only the teeth come out. Alternatively, the soft tissue may be isolated from the oxidant used in the whitening process by covering the soft tissue with a polymerizable composition that is shaped to conform to the gingival contour and then cured by exposure to a high intensity light source. Once the soft tissue is isolated and protected, the operator can apply the oxidant directly on the colored tooth surface for a certain period of time or until a sufficient change in tooth color occurs. Typical results obtained using in-office tooth whitening agents range from about 2 to 3 shades (measured with the VITA Shade Guide (VITA Zahnfarbik)).

The tooth shades of the Vita shade guides range from very bright (B1) to very dark (C4). A total of 16 tooth shades make up all the areas of color between these two endpoints for luminance class. Patient satisfaction with the tooth whitening procedure increases with the number of tooth shades achieved, and generally the minimum allowable change is preferably about 4-5 vita shades.

For dental hygiene products for whitening teeth, it is desirable to provide dental hygiene products that use an adhesive hydrogel comprising a whitening agent for removing pigmentation from an individual's teeth. In addition, development of a product that provides a protective dressing for mucosal surfaces or provides for the delivery of an active agent, such as for example, delivery of an agent via mucous membranes to mucosal tissues, tooth surfaces, gums, mucous membranes and other oral tissues. This is constantly being demanded. There is a need for compositions that do not require the use of dental trays to provide contact between the active agent and the teeth or other oral surfaces. Such products would ideally produce minimal or no tooth sensitivity, minimize or eliminate the ingestion by the user, or the release of active agents that cause damage or irritation to the gums or mucous membranes of the mouth, and longer wear times, It will provide sustained dissolution of the active agent, improved efficacy, and allow the patient to tolerate discomfort well. It would also be desirable to provide a dental hygiene product that is a solid composition and self-adhesive but does not adhere to the user's fingers, or that is non-solid (eg, liquid or gel) and forms a film when dried. As a result, current dental hygiene products require a system to be worn, for example for a specific time of 30 minutes, before being removed by the user. The development of a product that can self erode after the release of activity or after achieving the desired therapeutic or cosmetic effect is desirable because the system will improve patient acceptance. The present invention focused on these needs.

One aspect of the invention relates to a hydrogel composition comprising a water swellable water insoluble polymer and a blend of complementary oligomers and hydrophilic aggregates capable of hydrogen bonding or electrostatic bonding to a hydrophilic polymer. Active agents such as tooth whitening agents can also be included. The composition further includes a backing member that erodes at a slower rate than the hydrogel in the wet environment. The hydrogel is solid and the backing member can be attached to the backing member prior to use. The hydrogel is also non-solid and can be attached to the backing member during use.

In a preferred embodiment, the water swellable water insoluble polymer is a cellulose ester or acrylate polymer and the hydrophilic polymer is poly (N-vinyl lactam), poly (N-vinyl amide), poly (N-alkylacrylamide), or their Complementary oligomers which are copolymers and blends and capable of hydrogen or electrostatic bonding to hydrophilic polymers are polyhydric alcohol polyalkylene glycols or carboxyl terminated polyalkylene glycols. Preferred active agents are whitening agents such as peroxides.

The composition optionally comprises a low molecular weight plasticizer, including fillers, preservatives, pH adjusters, softeners, thickeners, colorants (eg pigments, dyes, refractive particles, etc.), flavoring agents (eg sweeteners, flavorings), It may also include one or more additives selected from the group consisting of stabilizers, surfactants, reinforcing agents, and detackifiers.

In a preferred method of using the composition, the composition is a tooth whitening composition and is removed when the degree of whitening is achieved after it is applied to the teeth in need of whitening. 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 present invention relates to a composition comprising a water swellable water insoluble polymer, a blend of a complementary oligomer capable of hydrogen or electrostatic bonding to a hydrophilic polymer and a hydrophilic polymer, and an active agent. In one aspect the active agent is selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxy acids, and combinations thereof. The composition further comprises a backing member that erodes at a slower rate than the hydrogel.

Another aspect of the invention relates to a method of making a hydrogel film suitable for incorporation into an oral hygiene or transmucosal composition. The method produces a solution or gel of a water swellable water insoluble polymer, a hydrophilic polymer, and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to a hydrophilic polymer in a solvent, and depositing a layer of the solution on the substrate to coat it on the substrate. And heating the coated substrate to a temperature of about 80 to about 100 ° C. for about 1 to about 4 hours to provide a hydrogel film over the substrate.

In another method of forming the composition of the present invention, the method comprises melt processing a mixture 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 through an extruder The composition is extruded into a film of the desired thickness on a suitable substrate. The substrate may be an erosive backing member, or the composition may then be pressed or laminated to the erosive backing member. The method further includes filling the hydrogel film with an active agent, such as a whitening agent, to provide a tooth whitening composition.

The adhesive composition of the present invention provides many important advantages over the prior art. In particular, the composition is

(1) provide ease of handling;

(2) are easily modified during fabrication so that properties such as adhesion, absorbency, translucency, and swelling can be controlled and optimized;

(3) can be formulated to increase or decrease adhesion in the presence of moisture so that the composition is not wet until wet;

(4) minimize leakage of the active agent (if included) from the composition at the mucosal surface (eg, in the mouth of the user),

(5) can be prepared in a translucent form so that the user can see the degree of whitening without removing the hydrogel composition from the tooth or mucosal surface,

(6) minimize damage to the gums or mucous membranes in the mouth,

(7) can be worn comfortably and inconspicuous,

(8) easily removed from the tooth or mucosal surface, leaving no residue,

(9) prolong the period of wear or activity;

(10) can provide sustained controlled release of various active agents,

(11) can be formulated to erode after a predetermined time,

(12) can be formulated, for example, to deliver the active agent in only one direction towards the mucosal tissue, or in two directions, for example, towards the mucosal surface and the oral cavity, wherein the relative rate of delivery towards the mucosal surface and the oral cavity is preselected. One or more advantages, such as controlled by selecting a backing member having permeability.

Method for carrying out the invention

I. Definitions and Nomenclature

Before describing the present invention in detail, it is to be understood that the present invention is not limited to a particular hydrogel material or manufacturing process unless otherwise indicated, as it 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 should be noted that the singular forms used in the specification and the appended claims include plural forms unless the context clearly dictates. 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, and the reference to "plasticizer" refers to a combination or mixture of two or more different plasticizers as well as a single Plasticizers and the like.

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

The definition of “hydrophobic” and “hydrophilic” polymers is based on the amount of water vapor absorbed by the polymer at 100% relative humidity. According to this classification, the hydrophobic polymer absorbs only 1% by weight or less of water at 100% relative humidity (“rh”), the medium hydrophilic polymer absorbs 1-10% by weight of water, and the hydrophilic polymer is 10 More than weight percent water can be absorbed, and the hygroscopic polymer absorbs more than 20 weight percent water. A “water swellable” polymer is one that absorbs an amount of water that, when immersed in an aqueous medium, is at least 25% by weight of its own weight, preferably at least 50% by weight of its own weight.

The term “crosslinking” herein refers to a composition containing intramolecular and / or intermolecular crosslinks that occur through covalent or noncovalent bonds. "Non-covalent" bonds include both hydrogen bonds and electrostatic (ionic) bonds.

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

The term “hydrogel” is used in its ordinary sense to refer to a water swellable polymer matrix capable of absorbing significant amounts of water to form an elastic gel, wherein the “matrix” is a three-dimensional network of macromolecules held together by covalent or non-covalent crosslinking. to be. When placed in an aqueous environment, the dry hydrogel swells to an extent that is acceptable by the degree of crosslinking. Hydrogels are also erosive.

The term "erosion" in the term "hydrogel erosion" or "erosion" in the "erodible backing member" includes not only processes of erosion, dissolution, cleavage, and degradation, but also those materials often referred to as bioerodible or biodegradable. It is intended to include. Regardless of the mechanism by which the hydrogel and backing member are dissipated in the wet environment, the component of the backing member is preferably selected such that the backing member "erodes" at a slower rate than the hydrogel component.

The terms "active agent", "pharmaceutical active agent" and "drug" are used interchangeably herein to refer to a chemical substance or compound that induces a desired pharmaceutical physiological effect, and has a therapeutic, prophylactic or cosmetic effect. Formulations that are present. The term also includes pharmaceutically acceptable pharmacologically active derivatives and analogs of the active agents specifically mentioned herein, including but not limited to salts, esters, amides, prodrugs, active metabolites, clathrates, analogs and analogs. do. When the terms "active agent", "pharmaceutical active agent" and "drug" are used, they are understood to include not only the active agent itself but also pharmaceutically acceptable pharmacologically active salts, esters, amides, prodrugs, active metabolites, clathrates, homologues and the like. shall.

The term "teeth whitening composition" refers to a composition containing a hydrogel and a whitening agent as defined above.

The term “whitening agent” typically refers to an oxidizing agent such as peroxide or chlorite, which will be discussed in more detail below. In some instances, the whitening agent may be an enzyme or other catalytic means for removing pigmentation from the teeth. Whitening agents may include one or more additional whitening agents, surfactants, anti-flag agents, anti tartar and abrasives. Whitening agents may have additional therapeutic benefits.

The term "effective amount" or "therapeutically effective amount" of a cosmetically active agent means a nontoxic or sufficient amount of the cosmetically active agent that provides the desired cosmetic effect. The term "effective amount" or "therapeutically effective amount" of a drug or pharmaceutical active is intended to mean a nontoxic or sufficient amount of the drug or agent that provides the desired therapeutic effect. The effective amount will vary from subject to subject, depending on the age and general condition of the individual and the particular active agent or agents. Thus, specifying the exact effective amount is not always possible. However, an effective amount suitable for any individual can be determined by one of ordinary skill in the art using routine experimentation. In addition, the precise effective amount of the active agent incorporated into the composition or dosage form of the present invention is not critical so long as the concentration is within a range sufficient to allow for easy application of the formulation so that the amount of active agent within the therapeutically effective range is delivered. not.

The term "surface" in the term "oral" surface or "body surface" refers to mucosal body surfaces (eg, sublingual glands, cheeks, vagina, rectum, urethra), as well as surfaces in and around the oral cavity (eg, teeth, Lips, gums, mucous membranes). These surfaces are typically located where referred to herein as "wet" environments.

A "mucosal" drug delivery involves the drug passing through mucosal tissue (eg, sublingual glands, cheeks, vagina, rectum, urethra) into the bloodstream of an individual and administering the drug to the mucosal tissue surface of the individual providing a systemic effect. Means that. The term "mucosal administration" is intended to include both local and systemic effects and thus includes topical administration that delivers a local agent to the mucosa to provide a local effect, eg, in the treatment of various mucosal tissue disorders.

The terms "tack" and "tack" are qualitative. As used herein, however, the terms "substantially non-sticky", "slightly sticky" and "sticky" can be quantified using the values obtained in the PKI or TRBT sticky determination methods as described below. "Substantially non-sticky" means a hydrogel composition having a tack value of less than about 25 g-cm / sec, and "slightly tack" means a tack value of about 25 g-cm / sec to about 100 g-cm / sec. By means of a hydrogel composition having, "adhesive" means a hydrogel composition having an adhesive value of 100 g-cm / sec or more.

The term "water insoluble" refers to a compound or composition having a solubility in water of less than 5% by weight, preferably less than 3% by weight, more preferably less than 1% by weight (measured in water at 20 ° C).

The term "translucent" is used herein to mean a material through which light can penetrate an object or an image through the material. The translucent material may be “transparent” or “transparent”, meaning optically transparent material herein. The term "translucent" means a material that is not "opaque" where no object or image is visible through the material.

II . Hydrogel  Composition

The composition of the present invention is a single phase hydrogel comprising a water swellable water insoluble polymer and a blend of hydrophilic polymer and complementary oligomer, and optionally an active agent such as a whitening agent. Both the water swellable water insoluble polymer and the oligomer may have hydrogen or electrostatic bonds to the hydrophilic polymer.

The composition also includes a backing member comprising a polymer composition that erodes at a slower rate than the hydrogel in a wet environment.

Water swellable water insoluble polymers, ie polymers that can swell when immersed in an aqueous solution but are insoluble in water in the selected pH range (generally below pH 5.5) are cellulose esters, alginic acid, or acrylate polymers. The term "acrylate polymer" is intended to include acrylate and acrylate based polymers and copolymers and is an acrylic acid or acrylic acid ester polymer. When immersed in water or an aqueous solution, the polymer generally swells at least 25% by weight, preferably at least 50% by weight of its own weight. In some embodiments using certain hydrophilic polymers, the composition can swell by 1400% by weight of its dry weight.

In one embodiment, the composition is a tooth whitening composition wherein the whitening agent acts to whiten the tooth surface to which the composition is applied. However, the whitening agent may have other uses, for example, as a therapeutic or other type of cosmetic treatment, such as cosmetic treatment for skin whitening. Thus, the compositions described herein may find use as pharmaceutical compositions that are applied to body surfaces (eg, teeth, nails, skin, mucous membranes, etc.) for the treatment of disease states. For example, hydrogen peroxide is not only a whitening agent but also has antibiotic and anti-acne properties. The present invention therefore also contemplates treating infections and acne by applying the hydrogen peroxide containing composition of the present invention to the body surface. Other disease states include, but are not limited to, fungal infections, acne, wounds, skin whitening, and the like. In addition, a number of active agents can be incorporated into the compositions of the present invention to treat various diseases affecting the oral cavity.

A. Water swellability Water insoluble  polymer

In the solid composition, the water swellable water insoluble polymer comprises about 1-20% by weight, preferably about 6-12% by weight of the composition, and the hydrophilic polymer is about 20-80% by weight of the composition, preferably about 40- 60% by weight, the complementary oligomers comprise about 10-50%, preferably about 15-35%, by weight of the composition, and the active agent, if present, is about 0.1-60%, preferably about 1, of the composition Constitute -30% by weight. Optimally, the complementary oligomers comprise about 10-80% by weight, preferably about 20-50% by weight of the hydrophilic polymer / complementary oligomer blend.

In non-solid compositions, the water swellable water insoluble polymer comprises about 0.1-20% by weight, preferably about 2-6% by weight of the composition, and the hydrophilic polymer is about 1-40% by weight of the composition, preferably about 4 -10% by weight, the complementary oligomer comprises about 0.1-20% by weight, preferably about 0.5-10% by weight of the composition, and the active agent, if present, is about 0.1-60% by weight of the composition, preferably about 1-40 weight%. Optimally, the complementary oligomers comprise about 1-85% by weight, preferably about 5-50% by weight of the hydrophilic polymer / complementary oligomer blend.

The adhesion profile can be adjusted based on the type of polymer, composition ratio, and water content in the blend. The water swellable water insoluble polymer is chosen to provide the desired adhesion profile for hydration. That is, when the water-swellable water-insoluble polymer is a cellulose ester, the composition generally loses adhesion as the adhesive or composition absorbs moisture prior to contact with water (eg, a wet surface). When the water swellable water insoluble polymer is an acrylate polymer or copolymer, there is generally provided a composition that is substantially non-tacky or tacky when contacted with a wet surface prior to contact with water.

Water-swellable Water-insoluble polymers may swell to some extent when immersed in an aqueous liquid, but are insoluble in water. Hydrophilic polymers can act to help dissolve the water insoluble polymer. The polymer may be a cellulose ester such as 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. These cellulose esters are described in U.S. Pat. Commercially available cellulose esters suitable for the present invention include CA 320, CA 398, CAB 381, CAB 551, CAB 553, CAP 482, CAP 504 (Eastman Chemical Company, Kingsport, Tenn.). Such cellulose esters typically have a number average molecular weight of about 10,000 to about 75,000.

In general, cellulose esters comprise a mixture of cellulose and cellulose ester monomer units, for example commercial cellulose acetate butyrate contains cellulose acetate monomer units as well as cellulose butyrate monomer units and non-esterified cellulose monomer units, while Acetate propionate contains monomeric units such as cellulose propionate. Preferred cellulose esters herein are cellulose acetate propionate compositions and cellulose acetate butyrate compositions having butyryl, propionyl, acetyl, and non-esterified (OH) cellulose in the amounts shown below.

Acetyl (%) OH (%) MW (g / mol) T _g (℃) T _m (℃) Cellulose acetate butyrate 17-52% Butyrate 2.0-29.5 1.1-4.8 12,000-70,000 96-141 130-240 Cellulose acetate propionate 42.5-47.7% Propionate 0.6-1.5 1.7-5.0 15,000-75,000 142-159 188-210

Preferred molecular weight, glass transition temperature (T _g ) and melting point (T _m ) are also shown. Suitable cellulosic polymers are also typically from about 0.2 to about 3.0 deciliters / gram, preferably about about when measured on a 0.5 gram sample in 100 ml of a 60/40 weight ratio solution of phenol / tetrachloroethane at a temperature of 25 ° C. Have an intrinsic viscosity (IV) of 1 to about 1.6 deciliters / gram. When prepared using solvent casting techniques, the water swellable water insoluble polymer should be chosen to provide greater cohesion and thus facilitate film formation (generally, for example, cellulose acetate propionate is preferred to cellulose acetate butyrate). Tends to improve cohesion even more).

Other preferred water swellable polymers are generally acrylate polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and / or other vinyl monomers. Suitable acrylate polymers are copolymers sold under the trade name "Eudragit (provided by Rom Parma, Germany)". Eudragit ^® series E, L, S, RL, RS and NE copolymers are available in organic solvents or dissolved in aqueous dispersions or as dry powders. Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as 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 in the form of spray drying of Eudragit L 30D-55 which can be reconstituted with water). The molecular weight of Eudragit L 30D-55 and Eudragit L 100-55 copolymers with a ratio of free carboxyl groups to ester groups of approximately 1: 1 is approximately 135,000 Da. Eudragit L 100-55 copolymers are generally insoluble in aqueous fluids below pH 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 less than pH 5.5, but unlike Eudragit L 30D-55, poorly dissolved at pH 5.5 to 7.0. The copolymer is dissolved at pH 7.0 and above. Eudragit L 100 can also be used, having a pH dependent solubility profile between Eudragit L 30D-55 and Eudragit S-100, as long as it is insoluble below pH 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 may be replaced with other acceptable polymers having similar pH dependent solubility properties. Other suitable acrylate polymers are methacrylic acid / ethyl acrylate copolymers available under the trade name “Kollicoat” (BASF AG, Germany). For example, Colicoat MAE has the same molecular structure as Eudragit L 100-55.

If the water swellable polymer is an acrylic acid or an acrylate polymer, a hydrogel that can be reversibly dried, i.e., after removal of water and any other solvents, can be reconstituted in its original state by adding water. Is provided. In addition, hydrophilic hydrogels made from acrylic acid / acrylate water swellable polymers are generally substantially non-tacky prior to contact with water, but tacky upon contact with wet surfaces such as the surface of teeth, such as those found in the mouth. . This property, which is non-tacky prior to contact with water, makes it possible to position or reposition the selected surface before or as the hydrogel becomes tacky. Once hydrated, the hydrogel becomes tacky and adheres to the surface of the tooth or mucosal surface.

In addition, although the ratio of acrylate polymer to hydrophilic polymer / complementary oligomer blend can be selected so that the rate and extent of swelling in an aqueous environment has a predetermined pH-dependency, the acrylate-containing composition may have a water or other aqueous liquid of less than pH 5.5. When the hydrogel composition is soaked in, it can generally provide a swelling in the range of about 400% to 1500%. This feature also provides retroactive incorporation of whitening agents or other active agents, such as filling the composition with peroxides, peroxy acids, chlorites, stabilizers, flavoring agents, and the like.

Conversely, when incorporating cellulose ester as a water swellable polymer, the hydrogel becomes tacky prior to application to the wet surface, but becomes non-tacky when absorbing water. It will be appreciated that such compositions may be desirable if a decrease in tack is desired when finally removing the product from the tooth.

Another suitable water swellable water insoluble polymer is alginic acid, which is water insoluble in water below pH 5.5, but can absorb and swell water.

B. Hydrophilic Polymer

The second component of the hydrogel composition is a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer. Referencing this as a "blend" is intended to mean that the interaction of the hydrophilic polymer and oligomer dominates the hydrogel properties. However, the addition of a water swellable water insoluble polymer helps to tailor the properties of the blend to obtain a single phase hydrogel with the desired properties. This alignment can be achieved by the selection of a particular water swellable water insoluble polymer, or by the inclusion of a specific amount of polymer, or even by the timing of adding the polymer to other components (hydrophilic polymers, complementary oligomers, active agents, etc.) during manufacture. have.

Hydrophilic polymers are generally relatively high molecular weight polymers and complementary oligomers are generally low molecular weight polymers. In the solid composition, the water swellable water insoluble polymer comprises about 1-20% by weight, preferably about 6-12% by weight of the composition, and the hydrophilic polymer is about 20-80% by weight of the composition, preferably about 40- 60% by weight, the complementary oligomer comprises about 10-50% by weight of the composition, preferably about 15-35% by weight, and the whitening agent is about 0.1-60% by weight of the composition, preferably about 1-30 It comprises weight%. Optimally, the complementary oligomers comprise about 10-80% by weight, preferably about 20-50% by weight of the hydrophilic polymer / complementary oligomer blend.

Suitable hydrophilic polymers include repeating units derived from N-vinyl lactam monomers, carboxy vinyl monomers, vinyl ester monomers, esters of carboxy vinyl monomers, vinyl amide monomers, and / or hydroxy vinyl monomers. Such polymers include, for example, poly (N-vinyl lactam), poly (N-vinyl acrylamide), poly (N-alkylacrylamide), substituted and unsubstituted acrylic and methacrylic acid polymers (e.g., polyacrylic acid and Polymethacrylic acid), polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof, and copolymers with other types of hydrophilic monomers (eg, vinyl acetate).

Poly (N-vinyl lactams) useful herein are preferably non-crosslinked copolymers of N-vinyl lactam monomer units or N-vinyl lactam monomer units, which constitute the majority of the total monomer units of poly (N-vinyl lactam) copolymers. Is a non-crosslinked homopolymer. Preferred poly (N-vinyl lactams) for use in the present invention include one or more of the following N-vinyl lactam monomers, namely N-vinyl-2-pyrrolidone, N-vinyl-2-valerolactam, and N-vinyl Prepared by the polymerization of -2-caprolactam. Non-limiting examples of useful non-N-vinyl lactam comonomers with N-vinyl lactam monomer units include N, N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethyl methacrylate, acrylamide, 2-acrylamide Fig. 2-methyl-1-propane sulfonic acid or a salt thereof, and vinyl acetate.

Poly (N-alkylacrylamides) include, for example, poly (methacrylamide) and poly (N-isopropyl acrylamide) (PNIPAM).

Polymers of carboxy vinyl monomers are typically acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and 1,2-dicarboxylic acids such as maleic acid or fumaric acid, maleic anhydride or mixtures thereof Preferred hydrophilic polymers in this class include polyacrylic acid and polymethacrylic acid, with polyacrylic acid being most preferred.

Preferred hydrophilic polymers here are poly (N-vinyl lactams), in particular polyvinyl pyrrolidone (PVP) and polyvinyl caprolactam (PVCap), poly (N-vinyl acetamide), in particular polyacetamide itself, carboxy vinyl Polymers of monomers, in particular 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, but the number average molecular weight of the hydrophilic polymer is generally about 100,000 to 2,000,000, more typically about 500,000 to 1,500,000. Oligomers are "complementary" to hydrophilic polymers in that they can make hydrogen or electrostatic bonds to the hydrophilic polymer. Preferably, the complementary oligomers have hydroxyl, amino or carboxyl termini. The oligomers typically have a glass transition temperature T _g of about −100 ° C. to about −30 ° C. and a melting point T _m of less than about 20 ° C. The oligomers can also be amorphous. The difference in T _g value between the hydrophilic polymer and the oligomer is preferably greater than about 50 ° C, more preferably greater than about 100 ° C, most preferably from about 150 ° C to about 300 ° C. Hydrophilic polymers and complementary oligomers must be compatible. In other words, it should be possible to form a uniform blend.

C. Complementary Oligomers

As mentioned above, complementary oligomers can have hydrogen or electrostatic bonds to hydrophilic polymers. Complementary oligomers may also be able to covalently bond to hydrophilic polymers. Complementary oligomers may also be capable of hydrogen or electrostatic bonding to the water swellable water insoluble polymer.

Generally, complementary oligomers will have a molecular weight of about 45 to about 800, preferably about 45 to about 600. Complementary oligomers are preferably low molecular weight polyalkylene glycols (molecular weights 200-600), such as polyethylene glycol 400, which can also act as low molecular weight plasticizers. Alternatively, different compounds may be incorporated as additional low molecular weight plasticizers, in which case any of the low molecular weight plasticizers described below may be used. In one embodiment of the invention, the complementary oligomer is a complementary low molecular weight or oligomer plasticizer containing at least two functional groups per molecule capable of hydrogen or electrostatic bonding to the hydrophilic polymer.

In some cases, complementary oligomers can also act as low molecular weight plasticizers. Alternatively, different compounds may be incorporated as additional low molecular weight plasticizers and, if included, will be present in approximately 30 to 35 weight percent of the composition.

Examples of suitable complementary oligomers include, but are not limited to, monomers and oligos such as low molecular weight polyhydric alcohols (eg glycerol or sorbitol), ethylene glycol and propylene glycol, including carboxyl and amino terminal derivatives of polyalkylene glycols. Alkylene glycols, ether alcohols (eg, glycol ethers), carbonic diacids, alkane diols that are butane diols to octane diols. Polyalkylene glycols, optionally carboxyl terminated, are preferred herein and polyethylene glycols having a molecular weight of about 200 to 600 are optimal complementary oligomers.

It will be understood from the above that a single compound, eg, low molecular weight polyalkylene glycol, such as polyethylene glycol having a molecular weight of about 200 to 600, can act as both a complementary oligomer and a low molecular weight plasticizer.

As discussed in U.S. Patent Application 2002/0037977 to Feldstein et al., The ratio of hydrophilic polymer to complementary oligomer in the aforementioned blends affects both adhesion and cohesion. As described in this patent application, the complementary oligomers reduce the glass transition of the hydrophilic polymer / complementary oligomer blends much larger than would be expected by the Fox equation of Equation 1 below.

In the formula, T _{g predicted} is the expected glass transition temperature of the hydrophilic polymer / complementary oligomer blend, w _pol is the weight fraction of the hydrophilic polymer in the blend, w _pl is the weight fraction of the complementary oligomer in the blend, T _{g pol} is the glass transition temperature of the hydrophilic polymer, T _{g pl} is the glass transition temperature of the complementary oligomer. As also described in the above patent application, the adhesive composition having an optimal adhesion and cohesion is T _g It can be prepared from complementary oligomers and hydrophilic polymers by selecting the components and their relative amounts to obtain the desired induction from _predicted . In general, to maximize adhesion, T _g The predetermined derived value from _predicted will be the maximum negative derived value, while to minimize adhesion, T _g Minimize any negative induction from _predicted .

Since the complementary oligomers themselves act as plasticizers, it is generally not necessary to add plasticizers to incorporate them. However, the inclusion of additional low molecular weight plasticizers in the composition is optional and may be advantageous in some cases. Suitable low molecular weight plasticizers are dialkyl phthalates, dicycloalkyl phthalates, represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di (2-ethylhexyl) -phthalate, diisopropyl phthalate, diamyl phthalate and dicapryl phthalate, Diaryl phthalates, and alkyl and aryl phosphates such as mixed alkyl-aryl phthalates, tributyl phosphate, trioctyl phosphate, tricresyl phosphate, and triphenyl phosphate, trimethyl citrate, triethyl citrate, tributyl citrate, acetyl Alkyl citrate and citrate esters such as triethyl citrate, and trihexyl citrate, dioctyl adipate (DOA), also called bis (2-ethylhexyl) adipate, diethyl adipate, di (2-methyl Dialkyl, such as ethyl) adipate, and dihexyl adipate Dialkyl tartrates such as diate, diethyl tartrate and dibutyl tartrate, dialkyl sebacates such as diethyl sebacate, dipropyl sebacate and dinonyl sebacate, diethyl succinate and dibutyl succinate Such as dialkyl succinate, glycerol diacetate, glycerol triacetate (triacetin), glycerol monolactate diacetate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate, ethylene glycol dibutyrate, tri Alkyl glycolates such as ethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate, alkyl glycerolates, glycol esters and glycerol esters, and mixtures thereof. Preferred low molecular weight plasticizers which are continuous hydrophilic phases are triethyl citrate, tributyl citrate, diethyl phthalate, and dioctyl adipate, most preferably dioctyl adipate.

The composition properties of the present invention can be easily controlled by adjusting one or more parameters during manufacture. For example, the adhesion of the composition can be controlled during manufacture to increase, decrease, or eliminate adhesion. This can be accomplished by changing the form and / or amount of the various components, or by changing the method of preparation. In addition, for the manufacturing process, compositions prepared using conventional melt extrusion processes are generally less sticky than compositions prepared using, but not necessarily, solution casting techniques. In addition, the degree of swelling of the hydrogel composition upon contact with water is determined by selecting different water swellable polymers and in these compositions containing a continuous hydrophilic phase, the ratio of the water swellable water insoluble polymer to the hydrophilic polymer / complementary plasticizer blend. It can be changed by adjusting. These compositions can vary in appearance from clear, transparent to translucent to opaque. In addition, certain compositions can be made easier by altering the relative amounts of components in the hydrophilic phase (eg, by reducing the amount of cellulose esters), or by methods of preparation (translucent hydrogels using solution casting rather than melt extrusion). Obtained) can be translucent. In such a method, the translucent composition allows the user to observe the therapeutic or cosmetic (eg, whitening) process during the therapeutic or cosmetic process, and when the desired effect has been achieved, eg For example, it allows the user to determine when the teeth are sufficiently whitened.

D. Activators

The composition may also include any pharmaceutical active agent useful for treating physiological conditions, including teeth, and surrounding tissues and other mucosal tissues. The active agent can be any substance that can be released from the composition to treat an undesirable physiological condition. Undesirable physiological conditions, including teeth or surrounding tissue that can be treated with the tool, include bad breath, periodontal and oral infections, periodontal injury, tooth decay, gingivitis, and other periodontal diseases. The active agent may be present in the hydrogel and / or backing member. In addition, various agents may be incorporated into the compositions of the present invention. For example, the backing may be filled with different active agents such as bad breath removers released into the oral cavity, while the hydrogel may contain tooth whitening agents released to the tooth surface.

Such agents may be present in cosmetically or therapeutically effective amounts. These include adrenergic agents, corticosteroids, corticosteroids, alcohol inhibitors, aldosterone antagonists, amino acids, ammonia detoxifiers, anabolic agents, stimulants, analgesics, androgenic agents, anesthetics, appetite suppressants, anorexia nervosa, Antagonists, anterior pituitary activators, and anterior pituitary inhibitors, antiparasitic agents, anti-acne agents, adrenergic agents, anti-allergic agents, amoeba inhibitors, antiandrogens, anemia agents, antianginal agents, stabilizers, arthritis agents, anti-asthmatic agents, anti-arteriosclerosis agents, Antimicrobials, anti-gallstones, anticholelithogenic agents, anticholinergics, anticoagulants, anticoccidal agents, anticonvulsants, antidepressants, antidiabetics, antidiabetic agents, antidiuretics, correctives, dyskinesia, antiemetics, Epilepsy treatments, antiestrogens, antifibrolytic agents, antifungal agents, glaucoma medications, anti-hemophilic agents, anti-hemopathy Urea, anti-hemorrhagic, antihistamine, antihyperlipidemic, antihyperlipidemic, antihypertensive, antihypertensive, infectious agent, anti-inflammatory, antikeratogenic agent, antimalarial agent, antibacterial agent, antimigraine, cell-like mitosis, Antifungals, antiemetics, antitumor agents, anticancer agents, antipneumocystic agents, compulsives, repellents, antiparkinsonian drugs, antipneumocystic agents, cytostatic agents, antiprostatic hypertrophy drugs ), Anti-ameases, anti-inflammatory drugs, anti-inflammatory drugs, antipsychotics, antirheumatic agents, anti-blood injections, anti-seborrheic agents, antispasmodics, antithrombotic agents, antitussives, anti-ulcer agents, anti-urolithic agents , Antiviral agent, appetite suppressant, benign prostatic hypertrophy drug, blood sugar control agent, aggregate absorption inhibitory agent, bronchial dilator, carbonic anhydrase inhibitor, cardioinhibitor, cardioprotectant, cardiovascular agent, cardiovascular agent, diarrhea agent, cholinergic agent, promotion Vaginal, cholinesterase active agents, anticoccidial agents, cognitive aids and stimulants, inhibitors, diagnostic aids, diuretics, dopaminergic agents, in vitro parasite control agents, emetic agents, enzyme inhibitors, estrogens, fibrinolytic agents, antioxidants, digestive tracts Exercise agents, glucocorticoids, gonadotropins, hair growth promoters, hemostatic agents, histamine H ₂ receptor antagonists, hormones, cholesterol lowering agents, hypoglycemic agents, hypolipidemic agents, hypotensive agents, HMGCoA reductase inhibitors, immunological agents, immunomodulators, immunomodulators, Immunostimulants, immunosuppressants, impotence aids, inhibitors, keratinants, LHRH agonists, hepatic disorders, lutein solubilizers, memory aids, metal function enhancers, mood inhibitors, mucolytic agents, mucosal protective agents, acid agents, nasal decongestants, Neuroleptics, neuromuscular blockers, neuroprotective agents, NMDA antagonists, non-hormone sterol derivatives, oxytocin agents, plasminogen activators , Platelet aggregation promoter antagonists, platelet aggregation inhibitors, post-stroke and head trauma treatment, enhancers, progestins, prostaglandins, prostar growth inhibitors, prothiotripins, psychotropic agents, radioactive agents, inhibitors, relaxants, energy use Modulators, scabs, hardeners, sedatives, hypnotics, selective adenosine A1 antagonists, serotonin antagonists, serotonin inhibitors, serotonin receptor antagonists, steroids, promoters, inhibitors, synergists, thyroid hormones, thyroid inhibitors, thyroid mimetics, mental stabilizers, instability Angina pectoris, uric aciduria, vasoconstrictor, vasodilator, traumatic, wound healing, xanthine oxidase inhibitor, and the like, but are only examples, but are not limited to these.

In one embodiment, the aforementioned hydrogel composition contains a whitening agent and therefore acts as a delivery system when applied to teeth. Release of the whitening agent “filled” in the present hydrogel composition typically includes both absorption of water and release of the agent through a swelling controlled diffusion mechanism. Whitening agent-containing hydrogel compositions can be used, for example, in a manner similar to topical pharmaceutical formulations.

Suitable tooth whitening agents include peroxides, metal chlorites, perborates, percarbonates, peroxy acids, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, calcium peroxide, magnesium peroxide, carbamide peroxide, and mixtures thereof. Preferred peroxides are hydrogen peroxide and carbamide peroxide. Other suitable peroxides are dialkyl peroxides such as t-butyl peroxide and 2,2 bis (t-butylperoxy) propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, t-butyl perbenzoate And peresters such as t-butyl per-2-ethylhexanoate, perdicarbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, cyclohexanone peroxide and methylethylketone perox Ketone peroxides such as seeds, and organic peroxides, including, but not limited to, hydroperoxides such as cumene hydroperoxide and tert-butyl hydroperoxide. The whitening agent is preferably a peroxide, such as hydrogen peroxide or carbamide peroxide, and most preferably hydrogen peroxide.

Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite, hypochlorite and chlorine dioxide. Preferred chlorite is sodium chlorite.

In another embodiment, the pharmaceutical active agent is, for example, nonsteroidal anti-inflammatory / painkiller, steroidal anti-inflammatory, local anesthetic, fungicide / disinfectant, antibiotic, antifungal, tooth sensitizer, fluoride caries preventive, anti tartar / anti-stone, Enzymes that inhibit the production of plaque, stones or cavities, abrasives such as pyrophosphate, ethylenediaminetetraacetic acid, metal chelates such as tetrasodium salts, antioxidants such as butylated hydroxyanisole, butylated hydroxytoluene, teeth And nutritional supplements to deliver locally to surrounding tissue.

Suitable nonsteroidal anti-inflammatory / analgesic agents are acetaminophen, methyl salicylate, monoglycol salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, flurlovif Lofen, pentacec, bufexamac, pyroxicam, phenylbutazone, oxyphenbutazone, clopezone, pentazocin, mepyrizol, and tiaraamide hydrogen chloride.

Suitable steroidal anti-inflammatory agents are hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluorocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone, dexamethasone acetate, betamethasone, betamethasone valerate, flumetason Hand, fluorometholone, budesonide, and beclomethasonedipropionate.

Suitable local anesthetics include dibucaine hydrogen chloride, dibucaine, lidocaine hydrogen chloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2- (diethylamino) ethyl ester hydrogen chloride, procaine hydrogen chloride, tetracaine hydrogen chloride, chloroprocaine hydrogen chloride, oxypro Caine hydrogen chloride, mepivacaine, cocaine hydrogen chloride, and piperocaine hydrogen chloride.

Suitable fungicides / disinfectants include thimerazole, phenol, thymol, benzalkonium chloride, benzetonium, chlorhexidine, providone iodide, cetylpyridinium chloride, eugenol, and trimethylammonium bromide.

Suitable antibiotics are penicillin, methicillin, oxacillin, cepharotin, cephaolidine, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptocin Mycin, gentamicin, bacitracin, and cycloserine. Suitable antifungal drugs include amphotericin, clotrimazole, econazole nitrate, fluconazole, griseofulvin, itraconazole, ketoconazole, myconazole, nystatin, terbinafine hydrogen chloride, undecenoic acid, and zinc undecenoate. .

Suitable tooth hypersensitivity reducing agents include potassium nitrate and strontium chloride. Suitable fluorine tooth decay agents include sodium fluoride, potassium fluoride and ammonium fluoride.

Further whitening agents are pyrophosphates, polyphosphates, polyphosphonates (e.g. ethane-1-hydroxy-1,1-diphosphonate, 1-azacycloheptan-1,1-diphosphonate, and Phosphates, such as linear alkyldiphosphonates), and tartar inhibitors, including salts thereof, linear carboxylic acids, and sodium zinc citrate, and mixtures thereof. Preferred pyrophosphate salts include dialkali metal pyrophosphate salts, tetraalkali metal pyrophosphate salts, and disodium dihydrogen pyrophosphate (Na ₂ H ₂ P ₂ O ₇ ), tetrasodium pyrophosphate (Na ₄ P). ₂ O ₇ ), and tetrapotassium pyrophosphate (K ₄ P ₂ O ₇ ) in hydrated or unhydrated form. Pyrophosphate salts are described in detail in Kirk & Othmer, Encyclopedia of Clinical Technology Third Edition, Volume 17, Wiley-Interscience Publishers (1982). Optionally, the whitening agent may also include tartar solubilizers such as betaine, amine oxides and quaternary as described in US Pat. No. 6,315,991 (Zofchak).

Enzyme agents that act to inhibit the formation of plaque, tartar, or tooth decay may also be useful in the composition. The enzyme preparation may be stored with a whitening agent or may be placed in different layers in the multilayer system as mentioned above. Suitable enzymes are proteases that are absorbed on the tooth layer or the first layer of plaque and destroy saliva proteins that form the envelope, lipases that destroy bacteria by breaking down proteins and lipids that form structural components of bacterial cell walls and membranes, adhesion of bacteria to teeth Amylase that prevents the development of tartar by disrupting dextranase, glucanohydrolase, endoglycosidase, and mucinase, and carbohydrate protein complexes that bind calcium to destroy the structure of bacteria that form a matrix for It includes. Preferred enzymes include any of commercial proteases, dextranases, glucanohydroases, endoglycosidases, amylases, mutanases, lipases, mucinases, and compatible mixtures thereof. In any embodiment, enzymatic whitening agents can be used.

Optionally, the enzymatic whitening agent is a peroxidase such as a peroxide produced in situ. If an enzymatic whitening agent or anti-flag agent is incorporated into the composition, the composition should allow the enzyme to remain in its active form, for example the pH should be approximately neutral and the peroxide may be omitted or contained in separate layers. .

Suitable nutritional supplements for local delivery to teeth and surrounding tissues include vitamins (e.g., vitamins C and D, thiamine, riboflavin, calcium pantothenate, niacin, folic acid, nicotinamide, pyridoxine, cyanocobalamin, para-aminobenzoic acid) , And bioflavonoids), and minerals (eg, calcium, phosphorus, fluorine, zinc, manganese, and potassium), and mixtures thereof. Vitamins and minerals useful in the present invention are described in Drug Facts and Comparisons (loose leaf drug information service), the Walters Kluer Company (St. Louis, MO), 1997, pp 3-17.

The composition may also include any cosmetically active agent. As used herein, a "cosmetic active agent" includes any substance that can be released from the composition to give a desirable alteration to the appearance of teeth or surrounding tissue or that imparts socially desirable properties to the user, such as, for example, bad breath removal. do. For example, cosmetically active agents can be bad breath removers or agents that affect the whitening or bleaching of teeth. Recognizing that the color of a tooth may be important or desirable in some cultures or in certain parts of Western society, the cosmetically active agent may also be any agent that imparts color or color tone to the tooth.

Additional whitening agents can be included in the composition. For example, surfactants such as detergents may also be present and will work with the whitening agents described above to provide a brighter appearance of the teeth.

Among these embodiments, the tooth whitening composition of the present invention preferably comprises a peroxide for tooth whitening and includes fillers, preservatives, pH adjusters, emollients, thickeners, colorants, pigments, dyes, refractive particles, stabilizers, reinforcing agents It may also include conventional additives such as pharmaceutical preparations, flavor or bad breath removers and permeation enhancers. In these embodiments where the adhesion is reduced or eliminated, conventional antitack agents may also be used. These additives, and amounts thereof, are selected so as not to significantly interfere with the chemical or physical properties of the tooth whitening composition or to impede the delivery of tooth whitening agents that may be included in the composition. These additional ingredients include coloring compounds, food additives, flavors, sweeteners, and preservatives.

E. Other Ingredients

Chemicals Used in Food Processing, Pub. No. 1274, National Academy of Sciences, pages 63-258, any natural or synthetic flavor or food additive may be included in the compositions of the present invention. Suitable flavoring agents include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils and oleoresin known in the art. The amount of flavoring used depends on the taste, flavor form, individual taste, and the desired intensity. Preferably, the composition comprises about 0.1 to 5 weight percent flavoring agent.

Sweeteners useful in the present invention include sucrose, fructose, aspartame, xylitol and saccharin. Preferably, the composition comprises sweetener in an amount of about 0.001 to 5.0 weight percent.

Suitable substrates may be translucent to make the composition inconspicuous when worn. However, the substrate or composition may optionally be colored so that the composition is easily visible when worn. Preferably, for coloring purposes, the color will be present in the substrate. For example, the substrate may be colored in a bright or vibrant color that the consumer is happy with. Thus, the substrate may comprise colored compounds such as, for example, dyes, pigments or materials which can be colored when added to the material forming the substrate.

For example, coloring compounds commonly used in foods, drugs, or cosmetics associated with the human body, in particular food additives licensed for use in foods classified as "approved" or "approved", may be used to color substrates. Can be. The coloring compounds used to color the substrate can be derived from natural sources such as vegetables, minerals or animals, or can be artificial counterparts of natural derivatives.

 Coloring compounds currently approved for use in food and ingested drugs under the Food Drug & Cosmetic Act include FD & C Red Number 3 (sodium salt of tetraiodofluorescein), Foodless 17 (6). -Hydroxy-5-{(2-methoxy-5-methyl-4-sulfophenyl) azo} -2-disodium salt of naphthalenesulfonic acid), food yellow 13 (quinophthalone or 2- (2-quine) Sodium salt of a mixture of mono and disulfonic acids of indandione), FD & C yellow number 5 (sodium salt of 4-p-sulfophenylazo-1-p-sulfophenyl-5-hydroxypyrazole-3 carboxylic acid ), FD & C yellow number 6 (sodium salt of p-sulfophenylazo-B-naphthol-6-monosulfonate), FD & C green number 3 (4-{[4- (N-ethyl-p-sulfobenzylamino)- Disodium salt of phenyl]-(4-hydroxy-2-sulfonium-phenyl) -m ethylene}-[1- (N-ethyl-Np-sulfobenzyl) -3,5-cyclohexadieimine]), FD & C blue number 1 (dibenzyldiethyl-diaminotriphenylcarbinolt Disodium salt of risulfonic acid unhydrite), FD & C blue number 2 (sodium salt of disulfonic acid of indigotin), FD & C red number 40, orange B, and citrus red number 2 dyes and combinations of various ratios thereof .

Coloring compounds exempted from FDA approval include: anatoto extract, beta-apo-8'-carotenal, beta carotene, beet powder, canthaxanthin, caramel color, carrot oil, cochineal extract (carmine ), Baked, partially skimmed cooked cotton flour, ferrous gluconate, fruit juice, grape extract, grape husk extract (enosiana), paprika, paprika oleoresin, riboflavin, saffron, turmeric, turmeric oleoresin, Vegetable juices, and combinations thereof in various proportions.

The form of the colored compound used in the composition preferably comprises a dye type additive, but may also include a lake type which is compatible with the material comprising the substrate. Water-soluble dyes provided in the form of powders, granules, liquids or other specific objects can be used according to the method. Preferably, the "lake", or water insoluble form, dye is used for coloring the substrate. For example, when a suspension of coloring compound is used, rake additives may be used. Suitable water-insoluble dye lakes provided by adding calcium or aluminum salts of FD & C dyes on alumina include FD & C Green # 1 Lakes, FD & C Blue # 2 Lakes, FD & C R & D # 30 Lakes and FD & C # Yellow 15 Lakes.

Other suitable coloring compounds include non-toxic water insoluble inorganic pigments such as titanium dioxide, chromium oxide green, ultramarine blue and pink and ferric oxide. Such pigments preferably have a particle size of about 5 to about 1000 microns, more preferably about 250 to about 500 microns.

The concentration of the colored compound in the substrate is preferably about 0.05 to 10% by weight, more preferably about 0.1 to 5% by weight.

In order to have various colors therein, one or more colored compounds may be present in the substrate. These various colors can be patterned into stripes, dots, swirls, or any other design that the consumer is happy with. Coloring compounds can also be used with other appearance enhancing materials such as glitter particles.

Absorbent fillers may be advantageously incorporated to control the degree of hydration when the adhesive is attached to the tooth surface. These fillers include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesium silicate, magnesium aluminum silicate, hydrophobic starch, calcium sulfate, calcium stearate, calcium phosphate, calcium phosphate Clays such as dihydrate, laponite, woven and nonwoven paper and cotton materials. Other suitable fillers may be inert, ie substantially non-absorbent, and include, for example, polyethylene, polypropylene, polyurethane polyether amide copolymers, polyester and polyester copolymers, nylon and rayon. Preferred fillers are colloidal silicas such as Cab-O-Sil ^® (Cabot Corporation, Boston, Mass.).

Preservatives are, for example, p-chloro-m-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methyl ester, 4-hydroxybenzoic acid propyl ester, benzalkonium chloride, cetylpyridinium chloride , Chlorohexidine diacetate or gluconate, ethanol, and propylene glycol.

Compounds useful as pH modifiers may also be included such that the pH of the hydrogel composition matches the pH of the mouth environment and prevents minerals from leaking from the surface of the teeth, glycerol buffer, citrate buffer, borate buffer, phosphate buffer, or citric acid- Phosphate buffers, including but not limited to. In order to optimize whitening without demineralization of the teeth, calcium and / or fluorine salts may be included in the composition.

Suitable softeners are citric acid esters such as triethyl citrate or acetyl triethyl citrate, tartaric acid esters such as dibutyl tartrate, glycerol esters such as glycerol diacetate and glycerol triacetate, phthalic acid esters such as dibutyl phthalate and diethyl phthalate, And / or hydrophilic surfactants, preferably hydrophilic nonionic surfactants such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers, and polyethylene glycol sorbitan-fatty acid esters. .

Preferred thickeners herein are naturally occurring compounds or derivatives thereof, such as collagen, galactomannan, starch, starch derivatives and hydrolysates, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxy Cellulose derivatives such as oxypropyl methyl cellulose, colloidal silicic acid, and sugars such as lactose, saccharose, fructose and glucose. Synthetic thickeners such as polyvinyl alcohol, vinylpyrrolidone-vinylacetate copolymer, polyethylene glycol, and polypropylene glycol may also be used.

As mentioned above, the substrate may also be interposed or embellished with a decorative article, such as beads, rhinestones, or the like, so long as it does not interfere with the viscoelastic properties of the substrate required for suitable modification of the composition on the teeth. The substrate may also represent letters, words or pictures that please or interest the consumer.

F. Erosion Backing  absence

The erosive backing member consists of a polymer composition that is eroded at a slower rate than the hydrogel in a wet environment and is substantially non-tacky. There are many materials that can be used as the backing member, and non-limiting examples include acrylate polymers, cellulose derived polymers, cellulose esters, starch, alginic acid, alginates, polyamino acids. Combinations, ie blends of any of these different polymers, can also be used as backing member materials.

In one embodiment, the hydrogel is eroded within about 1 second to 24 hours after being placed in the wet environment, and in another embodiment the hydrogel is eroded within about 10 seconds to 8 hours after placement. In another embodiment, the backing erodes within about 12 hours after the hydrogel is eroded, whereas in one embodiment, the eroding backing member is eroded about 12-24 hours after the hydrogel is eroded. The erosive backing member material, when used, may be selected to erode slightly slower than the hydrogel composition or at about the same rate (eg, when both erode within about 24 hours), but preferably slower than the hydrogel composition. Is selected to erode. In one embodiment, the eroding backing member erodes at least about 200% slower than the hydrogel, in another embodiment the backing erodes at least about 100% slower, in other embodiments the backing erodes at least about 50% slower, and further In another embodiment of the backing erodes at least about 25% slower than the hydrogel.

Suitable acrylate polymers are described above as water swellable water insoluble polymers, and non-limiting examples include acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, and / or ) Other polymers formed from vinyl monomers. Preferred acrylate polymers are Eudragit ^® copolymers (copolymers of methacrylic acid and methyl methacrylate) such as Eudragit ^® series E, L, S, RL, RS and NE copolymers. As mentioned above, these Eudragit polymers may also find use as hydroswellable water insoluble polymer components of hydrogels. Since Eudragit polymers are available in different grades with various pH dependent solubility and permeability characteristics, the grades used for erosive backing can be selected to have lower solubility compared to the grades used for hydrogels. For example, when L 100-55 is selected for use in a hydrogel, Eudragit L 100 can be used for backing, and when Eudragit L 100 is used for a hydrogel, Eudragit S 100 is used for backing. Can be used. In addition, mixtures of Eudragit polymers or other polymers and mixtures of excipients (eg buffers, pH adjusters) and Eudragit polymers can be used to adjust the erosion rate of the backing member to the hydrogel.

Suitable cellulose derived polymers include, but are not limited to, hydrate cellulose (cellophane), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxy Methylcellulose (CMC), and sodium carboxymethylcellulose (Na-CMC). Preferred celluloses include hydrate cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, and mixtures thereof.

Suitable cellulose esters are mentioned above as water swellable water insoluble polymers and include, but are not limited to, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose propionate, cellulose butyrate, cellulose propionate butyrate, cellulose di Acetates, cellulose triacetates, and mixtures thereof, polymers and copolymers. Representative cellulose ester copolymers include cellulose acetate butyrate and cellulose acetate propionate. Preferred cellulose esters are cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose propionate, cellulose butyrate, cellulose propionate butyrate, cellulose diacetate, cellulose triacetate, cellulose acetate butyrate, and cellulose acetate propionate And mixtures thereof.

Suitable starches are examples and not intended to limit, and includes a potato starch acetate, maize starch and the like (e. G., Cleveland RAM ^® starch (rocket (Roquette) service)), and mixtures thereof.

Suitable alginates include, but are not limited to, propylene glycol alginate, sodium alginate, calcium alginate, and mixtures thereof.

Suitable polyamino acids include, but are not limited to, polylysine, polyglycine, polyalanine, protamine, and mixtures thereof.

It should be understood that any active agent and other ingredients described in connection with the hydrogel composition may also be present in the backing member. For example, the backing may be filled with flavourant released into the oral cavity, while the hydrogel may contain an active agent released from the tooth surface or oral mucosa.

IV . Manufacturing process

The hydrogel compositions of the present invention are generally melt extrudable and thus can be prepared using simple blending and extrusion processes. The components of the composition are generally not necessarily necessary after weighing, but are mixed using, for example, Brabender or Baker Perkins Blender at elevated temperatures of about 90 to 140 ° C. If desired, solvents or water can be added. The resulting composition may be extruded using a single or twin screw extruder or may be finely divided. Alternatively, the components of the hydrogel composition can be melted all at once and then mixed before extrusion. The hydrogel composition can be extruded directly onto the eroding backing member. The hydrogel composition may also be extruded first, and then pressed or laminated to the backing member. Releaseable liners may also be included. The thickness of the hydrogel containing film produced for most purposes will be about 0.050 to 0.80 mm, more typically about 0.37 to 0.47 mm.

Alternatively, the composition is typically about 35-60% w in a suitable solvent, such as volatile solvents in which solution casting, e.g. ethyl acetate, or lower alkanols (e.g. ethanol, isopropyl alcohol, etc.) is particularly preferred. It can be prepared by mixing the components of the composition at a concentration of / v. The solution is cast on the erosive backing member or the releasable liner as above. Both the mixture and the casting are preferably carried out at ambient temperature. The backing member coated with the film is then baked for about 1 hour to about 4 hours, optimally about 2 hours, at a temperature of about 80 to 100 ° C, optimally about 90 ° C. Accordingly, one embodiment of the present invention provides a solution of a water swellable water insoluble hydrophilic polymer and a complementary oligomer capable of hydrogen or electrostatic bonding to the hydrophilic polymer and depositing the solution on the eroding backing member Providing a coating and heating the coated backing member at a temperature of about 80 ° C. to 100 ° C. for about 1 to 4 hours to provide a hydrogel film on the backing member for incorporation into a composition of the present invention. A method of making a suitable hydrogel film.

For the purpose of sticky hydrogel compositions, solution casting is the preferred process. Melt extrusion is preferred for the preparation of substantially non-tacky compositions. Although solution casting is typically preferred in these embodiments, both melt extrusion or solution casting techniques can be used to prepare the translucent composition. Thus, another embodiment of the present invention melt processing a mixture of a water swellable water insoluble polymer, a hydrophilic polymer, and a complementary oligomer capable of hydrogen or electrostatic bonding to the hydrophilic polymer to form an extrusion composition, Extruding the composition as a film of desired thickness on a suitable erosive backing member and filling the film with an aqueous solution of an active agent, such as peroxide, such that upon cooling a concentration of about 1 to 20% by weight of a whitening agent is obtained. It is a method of forming a composition comprising a.

The present invention also contemplates having a multilayer system comprising one or more additional hydrogel or nonhydrogel layers. For example, it may be aimed to include additional active agents which may be incompatible with the main active agent during storage. In this method, one layer may be the main active agent containing hydrogel layer and the other layers may contain additional active agent. These remaining layers may comprise the hydrogel compositions described herein or any other biocompatible formulation known in the art (eg, polyisobutylene, dimethylsiloxane, ethylene vinyl acetate, polyvinyl acetate, cellulose acetate, butyrate, Propionate, ethyl cellulose and water insoluble acrylates). In addition, it may be aimed to have an adhesive layer, for example a layer located directly on the tooth and a non-stick layer, for example an outer layer, located close to the lips, depending on the order of the arrangement of the layers. Another advantage of having a multilayer system is that the proportion of polymer used in the outermost layer can be varied such that non-tackiness is achieved to avoid including individual backing layers in the product.

In one embodiment, the composition is applied to a tooth, oral tissue or mucosal surface and then attached to said backing member, which is generally the adhesive composition of the present invention, which contains an external eroding backing member, optionally an additional active agent, that acts as the outer surface of the composition. Surface contact adhesive layer, and removable release liner. When removing the release liner, for example, the composition is applied to a surface to be treated, such as a tooth, and placed on the surface such that the oral surface contact layer contacts the tooth or other oral surface. In another embodiment, the composition is packaged without a release liner. Thus, once removed from the packaging, the composition is ready for use on the oral surface.

The hydrogel erosive backing member composition can include an additional substrate layer that can act as a major structural element during manufacture or use and can provide a support to the composition. The material used for the substrate should be inert and incapable of absorbing the hydrogel erosive backing member composition. In addition, the materials used in the substrate should allow the device to conform to the contours of the teeth or other body surfaces and should not be worn comfortably in the oral cavity without rubbing or irritating the lips or tongue. Examples of materials useful for the substrate are polyesters, polyethylenes, polypropylenes, polyurethanes and polyether amides. The substrate is preferably about 15 microns to about 250 microns thick, and may be colored, metallized if desired, or a mat finish suitable for recording may be provided.

In one embodiment, the substrate, although not essential, is preferably closed (ie, not “breathable”) and no active agent in the composition leaks through the layer and does not contact the mucous membranes of the mouth and gums. When preparing for use, the composition is wetted in advance so that the tack increases so that the composition adheres to the teeth. An advantage of this embodiment is that the active agent cannot substantially flow through the substrate and cause irritation to the active agent or to individuals who are sensitive to any unpleasant taste or sensation.

Other suitable substrate materials may be nonpolymeric materials such as waxes (eg microcrystalline or paraffin waxes) or wax / foam laminates. Paraffin waxes are low molecular weight straight chain hydrocarbons having a melting point of about 48-75 ° C. and a molecular weight of about 300-1400 g / mol, typically prepared by Fischer-Tropsch synthesis. Microcrystalline wax is seemingly flexible and amorphous, having higher tensile strength and smaller crystal size than paraffin wax. Microcrystalline waxes typically have a melting point of about 60-95 ° C. and a molecular weight of about 580-700 g / mol and may contain straight chain hydrocarbons, but mainly contain branched hydrocarbons and some cyclic compounds. The substrate material may also be an open cell foam such as polyurethane, polystyrene or polyethylene foam.

Alternatively, in another embodiment, the substrate is non-obstructive and can therefore be located on the tooth or other body surface and fully hydrated in situ.

The release liner is a disposable element that acts to protect the system before application. The release liner should be easily released from the contact adhesive and formed from a material that is impermeable to the active agent and the hydrogel composition. Release liners are typically treated with silicone or carbon fluoride and are typically made from polyester and polyethylene terephthalate.

Preferred compositions are typically prepared using acrylate polymers as water-insoluble water swellable polymers and blends of polyvinyl pyrrolidone and polyethylene glycol as blends of hydrophilic polymers and complementary oligomers capable of hydrogen or electrostatic bonding to hydrophilic polymers. do.

The adhesive film of the composition can be prepared by thermally melting and mixing the components together at about 100 ° C to 170 ° C. The film is extruded to the desired thickness on a suitable substrate. Alternatively, the components can be dissolved in a single solvent or solvent mixture and the solution can be cast on a release or backing film. The solvent is then evaporated to yield a hydrogel film.

One method of filling the composition with the active agent involves layering the desired active agent in an aqueous solution, such as a tooth whitening agent, on a hydrogel surface positioned on a suitable substrate, or placing the active agent directly on the substrate. The release liner is assembled on top of the composition and then forms a sandwich structure, and the whitening agent containing solution is absorbed into the composition due to the water swellable nature. Alternatively, the composition forming the layer on the substrate can be immersed in a solution containing the desired concentration of whitening agent, and the solution is absorbed into the composition. By measuring the ratio of weight that increases with absorption of the liquid, it is possible to determine and control the percentage by which the composition is filled with the active agent.

Another approach to filling the active agent into the composition is to add the active agent either as a solid or as a solution of the composition dissolved in a solvent. Lower drying temperatures are preferred when using this filling method, but the mixture is then typically cast and dried over a suitable substrate. The composition prepared in this manner can be dried at ambient temperature for about 1 hour to several days.

Typical film thickness is about 0.050 to 0.80 mm, preferably 0.25 to 0.50 mm. The thickness of the film is not critical and may vary depending on the concentration of the whitening agent incorporated into the film, the time the film is exposed to teeth, the level of convenience desired by the wearer, and the degree of coloring to be corrected.

V. How to use

Indeed, the composition may be removed from the package, the release liner (if included), and the adhesive layer applied to the teeth to be whitened (or the composition may be used for another purpose or another active agent may be used). If used, located on a wet body environment or on a wet surface). The system referred to herein may be provided in a variety of sizes, so that it can be used on all or any part of the tooth, on several teeth at once, or on any part of the oral or other wet areas.

The backing member is closed or impermeable so that while the user wears the composition for the desired time, the leakage of the active agent from the composition is prevented or reduced, i.e., the composition delivers the drug in one direction, for example only towards mucosal tissue. It can be formulated as. Alternatively, the backing member may be formulated to have a preselected permeability to provide drug delivery in two directions, for example, in the oral cavity as well as the mucosal surface. The level of permeability, ie selectivity, can also be used to control the rate of relative delivery to the mucosal surface and the oral cavity.

The composition may be maintained at a desired location for a short time, several hours, all day or overnight, such as moisture, and then removed when the desired degree of whitening or the desired therapeutic or cosmetic effect has been achieved. Alternatively, the composition may remain in position and may be completely eroded. Thus, in one embodiment of the present invention, the method of tooth whitening may only comprise applying the composition to a tooth in need of whitening, while in another embodiment the method is when the desired degree of whitening has been achieved. It may further comprise removing the composition.

If desired, a translucent composition can be provided and worn out of sight or inconspicuous of others. The system can also be devised without the active ingredient and can be used as a protective dressing, for example a wound dressing.

The composition may be worn for an extended time, but after wearing for a preselected time, typically from about 10 minutes to about 24 hours, the composition may be removed or eroded. For tooth whitening application, preferred times are from about 10 minutes to about 8 hours (eg overnight), and from 30 minutes to about 1 hour are also preferred embodiments. For other active agents, the therapeutically or cosmetically effective time can be readily determined based on the active agent used and the condition to be treated.

In one embodiment, the hydrogel is solid and attaches to the backing member during manufacture. Thus, the composition is applied in a single step. Alternatively, the hydrogel may be non-solid and manufactured and packaged separately from the backing member. In this case, the hydrogel is first applied by the user, and then the backing member is applied to the outer surface of the hydrogel by the user. In these embodiments, optionally by slightly moistening the composition or body surface prior to application, the user may apply normal hand pressure to the backing member with fingers and thumb tips to form the composition around the upper or lower teeth or other oral tissue. Can be. Assuming an average adult finger or thumb tip surface area of approximately one square centimeter, the pressure generated by the finger or thumb tip is about 100,000 to about 150,000 pascals (ie, about 3 lb or 1.36 kg) per square centimeter. . Pressure is typically applied to the composition by each finger and thumb tip for about 1 or 2 seconds. When the pressure applied to the backing member by the tip of the finger or thumb is removed, the composition remains in the form of the surface of the tooth and the surrounding soft tissue, and adheres to the surface and the surrounding soft tissue of the tooth on which the composition is formed.

When the user wants to remove the composition, the composition can be removed simply by peeling the composition off the surface of the tooth or other oral or body surface. If desired, the composition may be attached again for additional treatment time. Any residue left after is minimal and can be removed using conventional tooth or mouth cleaning methods.

In one embodiment of the invention, the composition is a solid, pressure sensitive adhesive and absorbs water.

The compositions may also be applied as non-solid compositions, for example liquids or gels. For example, a user may extrude from a tube on a finger to apply the composition to a tooth or other body surface, directly extrude from a tube onto a tooth, and apply the composition using a brush or other tool or the like. The erosive backing member may then be applied in individual steps after the liquid or gel is applied. After evaporation of the solvent, the liquid or gel composition is dried to form a matrix polymer film or gel on the body surface. In one embodiment of the liquid or gel film forming composition, the hydrogel contains sufficient water or other solvent to provide fluidity. In another embodiment of the composition, the polymer component of the liquid or gel composition is dissolved in the water-ethanol mixture at both ambient and refrigeration temperatures of about 4 ° C. and mixed upon evaporation of the solvent. In yet another embodiment of the liquid or gel film forming composition, the polymer composition has a Low Critical Solution Temperature of about 36 ° C. in an ethanol-water mixture. The resulting film (after solvent evaporation) is insoluble or slowly dissolved in saliva, preferably at body temperature, so that the contact between hydrogen peroxide and tooth enamel is long lasting. In the end, hydrogen peroxide must be stable not only in the liquid or gel composition but also in the polymer film when dried.

The practice of the present invention will use conventional polymer chemistry, adhesive preparation, and hydrogel preparation known to those skilled in the art unless otherwise indicated. Such techniques are explained fully in the literature.

While the invention has been described in connection with certain preferred embodiments thereof, it is to be understood that the following examples, as well as the foregoing description, are intended to illustrate the invention and are not intended to limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which this invention pertains.

The following examples are described to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the compounds of the invention, and are not intended to limit the scope of the inventions regarded by the inventors as inventions. Although an attempt has been made to ensure accuracy with respect to numbers (eg amounts, temperature, etc.), some errors and deviations should be considered. Unless indicated otherwise, parts are parts by weight, temperature is in degrees Celsius (° C.), and pressure is at or near atmospheric.

The following abbreviations and trade names are used in the examples.

Eudragit L 100-55 Methacrylic Acid Copolymer (Rohm America Inc.)

Eudragit L 100 Methacrylic Acid Copolymer (ROMA Americas Corporation)

PEG Polyethylene Glycol 400

PVP Kollidon ^® (Kollidon ^®) 90 polyvinylpyrrolidone (BASF (BASF))

<Example 1>

Preparation of Solid Composition

One embodiment of the tooth whitening composition could be prepared from the following components using a melt extrusion process.

Eudragit L 100-55 9% by weight

PVP 44 wt%

PEG 22 wt%

Hydrogen peroxide 6% by weight

19% by weight of water, stabilizer, pH adjuster

The components were melt processed in a Brabender single screw extruder as follows. Eudragit L 100-55 was first added to the extruder at a temperature of 100-150 ° C. followed by PVP and PEG. The composition was extruded to a thickness of 0.35 mm between the erosive backing member made of Eudragit S 100 and a polyethylene terephthalate release liner with a suitable plastic material if necessary. Hydrogen peroxide solution was added to the extruded film.

<Example 2>

Preparation of Non-Solid Compositions

A tooth whitening composition was prepared from the following ingredients.

Deionized Water 35.0 wt%

Ethanol 35.0 wt%

Eudragit L 100-55 4.00 wt%

PEG 1.00 wt%

PVP 7.00 wt%

Carbamide Peroxide 18.0% by weight

Sodium citrate 0.13% by weight

The compositions were mixed as follows in a Cole-Parmer high-torque low-speed lab mixer provided with a Teflon coated propeller (2 inches in diameter). Deionized water was mixed with ethanol and then PEG was added. Sodium citrate was then added under strong stirring conditions. Eudragit L 100-55 powder was added slowly (for 2-5 minutes) under vigorous stirring (500-600 rpm). After about 5-10 minutes (no need to wait for the Eudragit to dissolve), the PVP powder was added slowly (for 5 minutes). Strong stirring speed was maintained for 5-10 minutes. Carbamide peroxide powder was added (for 1-2 minutes) and the mixture was stirred (approximately 30 minutes at 800-900 rpm) to obtain a homogeneous solution. The solution was then stored for 2-5 hours to remove bubbles.

The tooth whitening composition could be packaged for use with the Eudragit RL 100 erosive backing member.

<Example 3>

Preparation of Non-Solid Compositions

A tooth whitening composition was prepared from the following ingredients.

Deionized Water 35.0 wt%

Ethanol 35.0 wt%

Eudragit L 100-55 2.50 wt%

PEG 1.92 wt%

PVP 6.00 wt%

Carbamide Peroxide 18.0% by weight

Sodium citrate0.08 wt%

Methocel A4C 1.50 wt%

The composition was mixed in a Cole Palmer high torque low speed lap mixer provided with a Teflon coated propeller (2 inches in diameter). Deionized water was mixed with ethanol and then PEG was added. Sodium citrate was then added under strong stirring conditions. Eudragit L 100-55 powder was added slowly (for 5 minutes) under strong agitation (500-600 rpm) followed by the slow addition of methocel A4C powder (for 5 minutes) under strong agitation (500-600 rpm). After about 10 minutes, the PVP powder was added slowly (for 5 minutes). Strong stirring speed was maintained for 5-10 minutes. Carbamide peroxide powder was added (for 1-2 minutes) and the mixture was stirred (approximately 30-60 minutes at 500-800 rpm) to obtain a homogeneous solution. The solution was then stored for 2-5 hours to remove bubbles.

The tooth whitening composition could be packaged for use with the Eudragit RS 100 erosive backing member.

Claims (59)

(a) (i) a water swellable water insoluble polymer, (ii) blends of complementary oligomers capable of hydrogen or electrostatic bonding to hydrophilic copolymers and hydrophilic polymers, and (iii) any active agent Hydrogel comprising a, and (b) a backing member comprising a copolymer composition that erodes at a slower rate than the hydrogel in a wet environment Composition comprising a. The composition of claim 1 wherein the water swellable water insoluble polymer is a cellulose ester, alginic acid, or acrylate polymer. 3. The composition of claim 2 wherein the cellulose ester comprises at least one cellulose polymer containing a non-esterified cellulose monomer unit, a cellulose acetate monomer unit, and a cellulose butyrate monomer unit or cellulose propionate monomer unit. The composition of claim 2 wherein the acrylate polymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, or ethyl methacrylate. The hydrophilic copolymer of claim 1, wherein the hydrophilic copolymer is poly (N-vinyl lactam), poly (N-vinyl amide), poly (N-alkylacrylamide), polyacrylic acid, polymethacrylic acid, polyvinyl alcohol, polyvinylamine And copolymers and blends thereof. The process of claim 1 wherein the complementary oligomers are polyhydric alcohols, monomeric and oligomeric alkylene glycols, polyalkylene glycols, carboxyl terminated polyalkylene glycols, amino terminated polyalkylene glycols, ether alcohols, alkanediols and carbonic diacids. Composition). The composition of claim 1, wherein the complementary oligomer is capable of hydrogen or electrostatic bonding to the water swellable water insoluble polymer. The composition of claim 1, wherein the backing member comprises a material selected from acrylate polymers, cellulose derived polymers, cellulose esters, starches, alginic acids, alginates, polyamino acids, and combinations thereof. The composition of claim 8 wherein the acrylate polymer is selected from polymers formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and ethyl methacrylate. 9. The cellulose derivative polymer according to claim 8, wherein the cellulose derivative polymer is selected from hydrate cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose and mixtures thereof. Composition. The cellulose ester of claim 8 wherein the cellulose ester is cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose propionate, cellulose butyrate, cellulose propionate butyrate, cellulose diacetate, cellulose triacetate, and mixtures thereof, polymers And a copolymer. The composition of claim 8 wherein the starch is selected from potato starch acetate, corn starch, and mixtures thereof. The composition of claim 8 wherein the alginate is selected from propylene glycol alginate, sodium alginate, calcium alginate and mixtures thereof. The composition of claim 8 wherein the polyamino acid is selected from polylysine, polyglycine, polyalanine, protamine, and mixtures thereof. The composition of claim 1 wherein the water swellable water insoluble polymer and the backing member comprise an acrylate polymer and the backing member acrylate polymer has a lower solubility than the water swellable water insoluble acrylate polymer. The composition of claim 1 wherein the relative amounts of the water swellable water insoluble polymer, the hydrophilic copolymer, and the complementary oligomer are selected to make the hydrogel translucent. The composition of claim 1 wherein the hydrogel is solid. 18. The composition of claim 17 comprising about 0.1-60% by weight of active agent. The composition of claim 17 comprising about 1-20% by weight of water swellable water insoluble polymer. The composition of claim 17 comprising about 20-80% by weight hydrophilic polymer. The composition of claim 17 comprising about 10-50% by weight of complementary oligomers. The composition of claim 1 wherein the hydrogel is a liquid or a gel. The composition of claim 22 comprising about 0.1-60% by weight of active agent. The composition of claim 22 comprising about 0.1-20% by weight of water swellable water insoluble polymer. The composition of claim 22 comprising about 1-40 weight percent hydrophilic polymer. The composition of claim 22 comprising about 0.1-20% by weight of complementary oligomers. The composition of claim 1 further comprising an absorbent filler. The composition of claim 1 wherein the composition is a pressure sensitive adhesive and absorbs water. The composition of claim 1, wherein the hydrogel is eroded for about 1 second to 24 hours after being placed in a wet environment. The composition of claim 29, wherein the hydrogel is eroded for about 10 seconds to 8 hours after being placed in a wet environment. The composition of claim 1, wherein the backing member is eroded in a humid environment for about 12 to 24 hours after the hydrogel is eroded. 32. The composition of claim 31, wherein the backing member is eroded in a humid environment about 12 hours after the hydrogel is eroded. The composition of claim 1, wherein the backing member erodes at least about 25% slower than the hydrogel. 34. The composition of claim 33, wherein the backing member erodes at least about 50% slower than the hydrogel. 35. The composition of claim 34, wherein the backing member erodes at least about 100% slower than the hydrogel. 36. The composition of claim 35, wherein the backing member erodes at least about 200% slower than the hydrogel. The composition of claim 1, wherein the hydrogel is solid and attached to the backing member prior to use. The composition of claim 1, wherein the hydrogel is a liquid or gel and attached to the backing member during use. The composition of claim 1 wherein the active agent is present. The composition of claim 39, wherein the backing member is impermeable to the active agent. The composition of claim 39, wherein the backing member is selectively permeable to the active agent. 40. The composition of claim 39, wherein the active agent is a whitening agent selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxy acids, and combinations thereof. 43. The composition of claim 42, wherein the peroxide is selected from the group consisting of hydrogen peroxide, calcium peroxide, magnesium peroxide, carbamide peroxide and mixtures thereof. 43. The composition of claim 42, wherein the peroxide is selected from the group consisting of dialkyl peroxides, diacyl peroxides, peresters, perdicarbonates, ketone peroxides, and hydroperoxides. 43. The composition of claim 42, wherein the metal chlorite is selected from the group consisting of calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, potassium chlorite, perchlorate, and dioxide chloride. The composition of claim 1 further comprising a flavourant. 47. The composition of claim 46, wherein the flavourant is selected from the group consisting of wintergreen, peppermint, spearmint, menthol, fruit flavor, vanilla, cinnamon, spices, flavor oils and oleoresin, and combinations thereof. The composition of claim 1 further comprising a sweetener selected from the group consisting of sucrose, fructose, aspartame, xylitol and saccharin. The method of claim 1, further comprising at least one additive selected from fillers, preservatives, pH adjusters, emollients, thickeners, colorants, pigments, dyes, refractive particles, flavoring agents, sweeteners, stabilizers, reinforcing agents, anti-sticking agents and permeation enhancers. A composition comprising. A tooth whitening method comprising applying the composition of claim 1 to a tooth in need of whitening. 51. The method of claim 50, further comprising removing the composition when the desired degree of whitening is achieved. 51. The method of claim 50, wherein the hydrogel is solid and attached to the backing member, wherein the applying step comprises applying the composition in a single step. 51. The method of claim 50, wherein the hydrogel is non-solid and the applying step comprises applying the hydrogel to the tooth followed by applying a backing member to the hydrogel. 51. The method of claim 50, wherein the composition comprises a release liner and the release liner is removed before applying the composition to the teeth. 51. The method of claim 50, wherein a desired degree of whitening is achieved after a predetermined time. The method of claim 55, wherein the predetermined time is about 10 minutes to about 24 hours. The method of claim 56, wherein the predetermined time is about 10 minutes to about 8 hours. 59. The method of claim 57, wherein the predetermined time is about 30 minutes to 1 hour. 51. The method of claim 50, wherein the composition can be worn for an extended time.