WO2013162404A1 - Bioadhésifs sensibles à la pression, hydrophiles, ayant une adhérence ciblée vis-à-vis des dents et compositions pour soins dentaires à base de ceux-ci - Google Patents

Bioadhésifs sensibles à la pression, hydrophiles, ayant une adhérence ciblée vis-à-vis des dents et compositions pour soins dentaires à base de ceux-ci Download PDF

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Publication number
WO2013162404A1
WO2013162404A1 PCT/RU2012/000377 RU2012000377W WO2013162404A1 WO 2013162404 A1 WO2013162404 A1 WO 2013162404A1 RU 2012000377 W RU2012000377 W RU 2012000377W WO 2013162404 A1 WO2013162404 A1 WO 2013162404A1
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composition
bioadhesive
film
polymer
peroxide
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PCT/RU2012/000377
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English (en)
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Mikhail Majorovich FELDSTEIN
Galina Grigorevna PEREPELITSA
Aleksej Removich KHOKHLOV
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Feldstein Mikhail Majorovich
Perepelitsa Galina Grigorevna
Khokhlov Aleksej Removich
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Application filed by Feldstein Mikhail Majorovich, Perepelitsa Galina Grigorevna, Khokhlov Aleksej Removich filed Critical Feldstein Mikhail Majorovich
Priority to EP12875126.0A priority Critical patent/EP2841045A4/fr
Publication of WO2013162404A1 publication Critical patent/WO2013162404A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/731—Cellulose; Quaternized cellulose derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K6/00—Preparations for dentistry
    • A61K6/30—Compositions for temporarily or permanently fixing teeth or palates, e.g. primers for dental adhesives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0208—Tissues; Wipes; Patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/22—Peroxides; Oxygen; Ozone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8129—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an alcohol, ether, aldehydo, ketonic, acetal or ketal radical; Compositions of hydrolysed polymers or esters of unsaturated alcohols with saturated carboxylic acids; Compositions of derivatives of such polymers, e.g. polyvinylmethylether
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8147—Homopolymers or copolymers of acids; Metal or ammonium salts thereof, e.g. crotonic acid, (meth)acrylic acid; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/817—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions or derivatives of such polymers, e.g. vinylimidazol, vinylcaprolactame, allylamines (Polyquaternium 6)
    • A61K8/8182—Copolymers of vinyl-pyrrolidones. Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/86—Polyethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • This invention relates generally to adhesive hydrogel compositions for tooth whitening, and more particularly relates to "smart" water-absorbing pressure sensitive bioadhesive films which manifest strong adhesion towards teeth but no adhesion towards other mucosal tissues in oral cavity.
  • Discoloration of the teeth is a widespread problem, occurring in two out of three adults. Dental discoloration is considered an aesthetic flaw, and can be particularly distressing or troublesome in situations and professions where showing clean and white teeth is essential.
  • a tooth is composed of an inner dentin layer and an outer, protective layer that is composed of hard enamel but slightly porous.
  • the natural color of the tooth is opaque to translucent white or slightly off-white.
  • Staining of teeth arises as a result of exposure to compounds such as tannins and other polyphenols. These compounds become trapped in or bound to the proteinaceous layer on the surface of teeth, and can penetrate the enamel and even the dentin. On occasion, staining can arise from sources within the tooth, such as tetracycline, which may become deposited in the teeth if administered to an individual when young.
  • an oxidizing agent such as hydrogen peroxide
  • tooth whitening compositions generally fall into two categories: (1) gels, pastes, and liquids, including toothpastes that are mechanically agitated at the stained tooth surface in order to affect tooth stain removal through abrasive erosion of surface stains; and (2) gels, pastes, or liquids that accomplish a tooth-bleaching effect by a chemical process while in contact with the stained tooth surface for a specified period, after which the formulation is removed.
  • an auxiliary chemical process which may be oxidative or enzymatic, supplements the mechanical process.
  • Some dental compositions such as dentrifices, toothpastes, gels, and powders contain active oxygen or hydrogen peroxide liberating bleaching agents.
  • bleaching agents include peroxides, percarbonates, and perborates of the alkali and alkaline earth metals or complex compounds containing hydrogen peroxide.
  • peroxide salts of the alkali or alkaline earth metals are known to be useful in whitening teeth.
  • a related class of compound, the peroxyacids has been used in laundry detergents to effectively whiten clothes, due primarily to their stability in solution and their specific binding abilities to certain types of stain molecules.
  • a number of stable, solid peroxyacids have been used, including diperoxydodecanoic acid and the magnesium salt of monoperoxyphthalic acid.
  • Other peroxyacids, such as peroxyacetic acid are available as solutions containing an equilibrium distribution of acetic acid, hydrogen peroxide, peroxyacetic acid, and water.
  • a peroxide donor such as sodium perborate or sodium percarbonate is formulated together with a peroxyacid precursor.
  • peroxide donor Upon contact with water, the peroxide donor releases hydrogen peroxide which then reacts with the peroxyacid precursor to form the actual peroxyacid.
  • peroxyacids created in situ include peroxyacetic acid (from hydrogen peroxide and tetraacetylethylenediamine) and peroxynonanoic acid (from hydrogen peroxide and nonanoyloxybenzene sulfonate).
  • Peroxyacids have also been used in oral care compositions to whiten stained teeth.
  • U.S. Patent No. 5,279,816 describes a method of whitening teeth comprising the application of a peroxyacetic acid-containing composition having an acid pH.
  • EP 545,594 Al describes the use of peroxyacetic acid in preparing a composition for whitening teeth.
  • the peroxyacetic acid may be present in the composition, or alternatively, may be generated in situ by combining a peroxide source with a peroxyacetic acid precursor during use.
  • U.S. Patent N°. 5,302,375 describes a composition that generates peroxyacetic acid within a vehicle in situ by combining water, acetylsalicylic acid and a water-soluble alkali metal percarbonate.
  • carbamide peroxide The most commonly used dental whitening agent is carbamide peroxide.
  • Carbamide peroxide had been used by dental clinicians for several decades as an oral antiseptic, and tooth bleaching was an observed side effect of extended contact time.
  • Over-the-counter compositions of 10% carbamide peroxide are available as GLY- OXIDE® by Marion Laboratories and PROXIGEL® by Reed and Carnrick, which are low-viscosity compositions that must be held in a tray or similar container in order to provide contact with the teeth.
  • a bleaching gel which is able to hold a comfortable-fitting dental tray in position for an extended time period is available under the trademark OPALESCENCE® from Ultradent Products, Inc. in South Jordan, Utah.
  • compositions In order for such compositions to stay in place, the compositions must be a viscous liquid or a gel.
  • the use of dental trays also requires that the tray be adapted for comfort and fit so that the tray will not exert pressure or cause irritation to the person's teeth or gums.
  • Such whitening compositions necessarily should be formulated so as to be sufficiently sticky and viscous to resist dilution by saliva.
  • a dental professional will construct a custom made dental bleaching tray for the patient from an impression made of the patient's dentition and prescribe the use of an oxidizing gel to be dispensed into the bleaching tray and worn intermittently for a period of from about 2 weeks to about 6 months, depending upon the severity of tooth staining.
  • oxidizing compositions usually packaged in small plastic syringes or tubes, are dispensed directly by the patient into the custom-made tooth-bleaching tray, held in place in the mouth for contact times of greater than about 60 minutes, and sometimes as long as 8 to 12 hours.
  • the slow rate of bleaching is in large part the consequence of the very nature of formulations that are developed to maintain stability of the oxidizing composition.
  • U.S. Patent No. 6,368,576 to Jensen describes tooth whitening compositions that are preferably used with a tray so that the composition is held in position adjacent to the person's tooth surfaces to be treated.
  • These compositions are described as a sticky matrix material formed by combining a sufficient quantity of a tackifying agent, such as carboxypolymethylene, with a solvent, such as glycerin, polyethylene glycol, or water.
  • U.S. Patent No. 5,718,886 to Pellico describes a tooth whitening composition in the form of a gel composition containing carbamide peroxide dispersed in an anhydrous gelatinous carrier, which includes a polyol, a thickener, and xanthan gum.
  • a tooth whitening composition that adheres to the teeth is described in U.S. Patent Nos. 5,989,569 and 6,045,81 1 to Dirksing.
  • the gel contains 30-85% glycerin or polyethylene glycol, 10-22% urea/hydrogen peroxide complex, 0- 12% carboxypolymethylene, 0-1% sodium hydroxide, 0-100% triethanolamine (TEA), 0- 40% water, 0-1% flavor, 0-15% sodium citrate, and 0-5% ethylenediaminetetraacetic acid.
  • the preferred gel according to Dirksing has a viscosity between 200 and 1 ,000,000 cps at low shear rates (less than one s "1 ), and is sufficiently adhesive so as to obviate the need for a tray.
  • Tooth sensitivity may result from the movement of fluid through the dentinal tubules, which is sensed by nerve endings in the tooth, due to the presence of glycerin, propylene glycol, and polyethylene glycol in these compositions. This can result in varying amounts of tooth sensitivity following exposure of the teeth to heat, cold, overly sweet substances, and other causative agents.
  • Prolonged exposure of teeth to bleaching compositions has a number of adverse effects in addition to that of tooth sensitivity. These adverse effects include leaching of calcium from the enamel layer at a pH less than 5.5; penetration of the intact enamel and dentin by the bleaching agents and risking damage to pulpal tissue; and dilution of the bleaching compositions with saliva resulting in leaching from the dental tray and subsequent ingestion by the user.
  • Some oxidizing compositions are applied directly to the tooth surface of a patient in a dental office setting under the supervision of a dentist or dental hygienist. Theoretically, such tooth whitening strategies yield faster results and better overall patient satisfaction.
  • oxidizing agents contained in these so called "in-office" compositions they can be hazardous to the patient and practitioner alike if not handled with care.
  • the patient's soft tissues (the gingiva, lips, and other mucosal surfaces) must first be isolated from potential exposure to the active oxidizing agent by the use of a perforated rubber sheet (known as a rubber dam), so that only the teeth protrude.
  • the soft tissue may be isolated from the oxidizers to be used in the whitening process by covering the soft tissue with a polymerizable composition that is shaped to conform to the gingival contours and subsequently cured by exposure to a high intensity light source.
  • the practitioner may apply the oxidizing agent directly onto the stained tooth surfaces for a specified period of time or until a sufficient change in tooth color has occurred.
  • Typical results obtained through the use of an in-office tooth whitener range from about 2 to 3 shades (as measured with the VITA Shade Guide, VITA Zahnfarbik).
  • the range of tooth shades in the VITA Shade Guide varies from very light (Bl) to very dark (C4).
  • a total of 16 tooth shades constitute the entire range of colors between these two endpoints on a scale of brightness.
  • Patient satisfaction with a tooth whitening procedure increases with the number of tooth shade changes achieved, with a generally accepted minimum change desirable of about 4 to 5 VITA shades.
  • compositions that do not require the use of dental trays to provide contact between the bleaching agent and the teeth are particularly desirable.
  • Such products ideally cause minimal or no tooth sensitivity, minimize or eliminate leakage of the whitening agent resulting in ingestion by the user or resulting in damage or irritation to the gums or mucous membranes of the mouth, provide for longer wear duration, sustained dissolution of the tooth whitening agent, improved efficacy, and are well tolerated by users.
  • tooth whitening dental care product that is a solid composition and self-adhesive film but that does not stick to the fingers of the user, or that is a non-solid (e.g., liquid or gel) and forms a film when dry.
  • a non-solid e.g., liquid or gel
  • compositions that adhere to the teeth for a prolonged period of time and release whitening agent gradually with controlled rate are described in U.S. Patent Applications Nos. 2003/0152528, 2003/0235549, 2004/0105834 and 2006/0171906 by P. Singh, G.W. Cleary, M.M. Feldstein, D.F. Bairamov at al.
  • the compositions are provided, wherein the formulation comprises a water-swellable, water-insoluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen or electrostatic bonding to the hydrophilic polymer, and a whitening agent, preferably a peroxide.
  • the compositions find utility as tooth whitening hydrogel or strip formulations and are applied to the teeth in need of whitening, and then removed when the degree of whitening has been achieved.
  • the tooth whitening composition is translucent, comprises a mixture of tooth whitening agents, with a first whitening agent selected so as to release peroxide gradually upon contact with moisture and produce an alkaline pH, and a second whitening agent selected so as to release peroxide rapidly upon contact with moisture.
  • the new tooth whitening composition provides sustained release of high levels of whitening agent and is moisture-activated without significant swelling.
  • a preferred system for applying the composition to the teeth is flexible, self-adhesive, and well-tolerated by users. Methods for preparing and using the compositions are also disclosed.
  • Crest 3D White Whitestrips ® Advanced Seal available from Procter & Gamble Company (see U.S. Patent Application No 2006/0171906 and PCT Application No WO 2006/069236 to P. Singh, E.S. Lee, A. Sagi, M.M. Feldstein, D.F. Bairamov).
  • New Crest Whitestrips ® Advanced Seal utilizes the CorplexTM technology that combines the principles of dermal pressure sensitive adhesives (PSAs) and bioadhesives (BAs) to create the perfect adhesive balance and hold the strip in place. The fundamentals of this technology were first described in G.W. Cleary, M.M. Feldstein, E.
  • the composition shows no or negligible adhesion to dry substrates.
  • the adhesion increases achieving high steady-state level in the range from 10 to 20 J/m 2 (see P.E. Kireeva, M.B. Novikov, P. Singh, G.W. Cleary, M.M. Feldstein, Tensile properties and adhesion of water absorbing hydrogels based on triple poly(N- vinyl pyrrolidone) I poly(ethylene glycol) I poly (methacry lie acid - co - ethylacrylate) blends, J. Adhesion Sci. Technol. 2007, vol. 21 JTs. 7, p. 531 - 557).
  • the CorplexTM adhesive platform in Advanced Seal tooth whitening strip Activated by naturally moisture in the mouth, such as saliva, the CorplexTM adhesive platform in Advanced Seal tooth whitening strip provides instant adhesion and instantly molds to teeth with no slipping in the course of moisture absorbtion and swelling. After use, the PSA film is easily removed from teeth with no mess and no residue.
  • a representative tooth whitening system of the prior-art invention is composed of an interior tooth whitening layer bisected by a nonwoven layer, such that the interior tooth whitening layer includes an upper region and a lower region.
  • the upper region is laminated to the outer backing layer, composed of a relatively hydrophobic, permeable polymer and containing 1.0 wt. % to 30.0 wt. % tooth whitening agent.
  • the outer backing layer provides the exterior surface of the system following application to the teeth.
  • Removable release liner covers the otherwise exposed surface of the lower region of the interior tooth whitening layer prior to use.
  • the suitable nonwoven mesh bisecting the interior whitening agent layer into two separate layers is normally polyamide, obtained from Spunfab.
  • the function of the outer backing member is to protect the multilayer tooth whitening system from adherence to mucous tissues of the tongue, gingiva and palate, and thus keep the strip on teeth.
  • the function of nonwoven mesh in adhesive layer is to prevent slipping the strip.
  • the Advanced Seal tooth whitening strip is four-layer device.
  • the special outer layer holds the strip securely on teeth.
  • the whitening layer delivers the same high- performance whitening ingredient used by professional dentists.
  • the inner mesh layer keeps the whitening ingredient firmly on teeth, preventing gel from spreading to other areas of the mouth.
  • the final release liner provides the strips with stable backing for easy application.
  • the Advanced Seal tooth whitening system comprises a flexible strip, or backing layer (also referred to herein as an "outer layer"), in contact with a tooth whitening composition of the invention.
  • the backing layer may comprise any suitable material, e.g., polymer, woven, non-woven, foil, paper, rubber, or a combination thereof, such as a laminate.
  • the backing layer may be erodible, as described in U.S. Patent Publication No. 2004/0105834.
  • the system will also include a removal release liner that covers the tooth whitening composition prior to use and prevents exposure of the composition to air.
  • the system includes two flexible, soft layers with differential permeability, the outer layer being measurably permeable but somewhat less permeable than the inner layer. Tooth whitening agent is present in both layers, with the outer layer essentially serving as an additional reservoir for the whitening agent(s).
  • the outer layer is relatively hydrophobic, such that the system is prevented from sticking to the lips and releasing any significant amount of hydrogen peroxide into the mouth in a direction away from the teeth.
  • the new Crest Whitestrips ® Advanced Seal is rather heavy multilayer device that includes normally two nontransparent members: the polyamide network in the interior adhesive layer and outer backing film.
  • This multilayer structure imparts to the strip appreciable heaviness that hampers user's capacity to speak on phone during the session of whitening the teeth.
  • availability of opaque layers makes the strip visible on teeth and creates inconvenience under its application outside home.
  • the new tooth whitening composition provides sustained release of high levels of whitening agent and is moisture- activated without significant swelling.
  • the preferred system for applying the composition to the teeth is flexible, self-adhesive to teeth but inadherent to mucosal tissues of oral cavity, invisible on teeth and generally well- tolerated by users, gradually eroding during long-term wear.
  • an improved tooth whitening strip is provided that is based on "smart" moisture-absorbing PSA that possesses high adhesion towards teeth but no adhesion to other wet mucosal tissues in oral cavity (tongue, gingival, palate).
  • a tooth whitening composition comprises at least one tooth whitening agent, or incorporates a mixture of tooth whitening agents, with a first whitening agent selected so as to release peroxide gradually upon contact with moisture and produce an alkaline or acidic pH, and a second whitening agent selected so as to release peroxide rapidly upon contact with moisture.
  • a tooth whitening composition that comprises an admixture of:
  • a first whitening agent that is inert in a dry environment but activated upon contact with moisture to release hydrogen peroxide
  • a second whitening agent that is inert in a dry environment but activated upon contact with aqueous base or acid
  • the water-swellable, water-insoluble polymer may be, by way of example, a cellulosic polymer such as a cellulose ester, an acrylic acid and/or acrylate copolymer, or a mixture of such polymers.
  • a mixture of acrylic acid and/or acrylate copolymers can be advantageously provided by combining an anionic copolymer with a cationic copolymer such that the copolymers ionically associate with each other, yielding a polymer matrix.
  • compositions generally, although not necessarily, also contain a crosslinked hydrophilic polymer, e.g., a covalently crosslinked hydrophilic polymer, a blend of a hydrophilic polymer and a relatively low molecular weight complementary oligomer that is capable of crosslinking the hydrophilic polymer via hydrogen bonding, or a combination thereof.
  • a crosslinked hydrophilic polymer e.g., a covalently crosslinked hydrophilic polymer, a blend of a hydrophilic polymer and a relatively low molecular weight complementary oligomer that is capable of crosslinking the hydrophilic polymer via hydrogen bonding, or a combination thereof.
  • a tooth whitening composition that comprises an admixture of:
  • a tooth whitening agent that is inert in a dry environment but activated in the presence of moisture
  • At least two water-swellable polymers wherein a first water-swellable polymer is a polyacid, a second water-swellable polymer is a polybase, and the polymers are ionically or H-bonded associated with each other to form a water-swellable, water- insoluble polymer matrix.
  • compositions contain a single tooth whitening agent that is moisture-activated.
  • compositions will also contain, in most instances, a crosslinked hydrophilic polymer as described above.
  • a tooth whitening composition comprises: 1.5 wt.% to 30 wt.% of a hydrophilic polymer composition composed of (a) a covalently crosslinked hydrophilic polymer, and/or (b) a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding thereto; 40 wt.% to 90 wt.% of at least one water-swellable, water-insoluble polymer; and at least one tooth whitening agent.
  • a hydrophilic polymer composition composed of (a) a covalently crosslinked hydrophilic polymer, and/or (b) a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding thereto; 40 wt.% to 90 wt.% of at least one water-swellable, water-insoluble polymer; and at least one tooth whitening agent.
  • the composition optionally comprises a low molecular weight plasticizer, and may also comprise at least one additive selected from the group consisting of fillers, preservatives, pH regulators, softeners, thickeners, colorants (e.g., pigments, dyes, refractive particles, etc.), flavorants (e.g., sweeteners, flavors), stabilizers, toughening agents and detackifiers.
  • a low molecular weight plasticizer may also comprise at least one additive selected from the group consisting of fillers, preservatives, pH regulators, softeners, thickeners, colorants (e.g., pigments, dyes, refractive particles, etc.), flavorants (e.g., sweeteners, flavors), stabilizers, toughening agents and detackifiers.
  • the tooth whitening composition is applied to the teeth in need of whitening, and then gradually erodes or removed when the degree of whitening has been achieved.
  • the tooth whitening composition is translucent, and the composition is removed when the user is satisfied with the degree of whitening achieved.
  • Yet another aspect of the invention pertains to a composition
  • a composition comprising a water- swellable, water-insoluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and an agent selected from the group consisting of peroxides, carbamide peroxide, metal chlorites, perborates, percarbonates, peroxyacids, and combinations thereof.
  • bioadhesive compositions with targeted adhesion to teeth contain a non-covalent complex of hydrophilic film-forming polymer with complementary polymer, oligomer or low- molecular weight compounds as a platform for tooth whitening products.
  • Such complexes can be formed by hydrogen or ionic bonding of the complementary components.
  • Another aspect of the invention relates to a method for preparing a hydrogel film suitable for incorporation into a tooth whitening composition (?).
  • This method comprises preparing a solution or a gel of a water-swellable, water-insoluble polymer, a hydrophilic polymer, and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, in a solvent; depositing a layer of the solution on a substrate to provide a coating thereon; and heating the coated substrate to a temperature in the range of about 80°C to about 100°C for a time period in the range of about 1 to about 4 hours, thereby providing a hydrogel film on the substrate.
  • the method further comprises loading the hydrogel film with the whitening agent, thereby providing the tooth whitening composition.
  • the "smart" adhesive tooth whitening compositions of the invention provide a number of significant advantages relative to the prior art.
  • the smart bio-PSA compositions :
  • (5) can be formulated so that tack increases or decreases in the presence of moisture so that the composition is not sticky until moistened;
  • (7) can be fabricated in translucent from, enabling the user to view the extent of whitening without removing the hydrogel composition from the teeth, or be invisible on the teeth;
  • (11) are amenable to extended duration of wear; and sustained and controlled release of the whitening agent;
  • (12) can be applied to teeth at any time, day and night, not limiting user's capacity talking on phone, to negotiate, drink water; (13) provide efficiency of manufacturing, eliminating the stages of lamination to backing film and incorporation of nonwoven mesh into adhesive layer, loaded with whitening agent.
  • polymers accepting protons in the course of hydrogen bonding with macromolecules containing complementary functional groups have been defined here as polybases.
  • polymers donating protons in the course of hydrogen bonding with macromolecules containing complementary functional groups have been defined here as polyacids.
  • hydrophobic and hydrophilic polymers are based on the amount of water vapor absorbed by polymers at 100 % relative humidity. According to this classification, hydrophobic polymers absorb only up to 1 wt. % water at 100% relative humidity (“RH"), while moderately hydrophilic polymers absorb 1 -10 wt. % water, hydrophilic polymers are capable of absorbing more than 10 wt. % of water, and hygroscopic polymers absorb more than 20 wt. % of water.
  • RH relative humidity
  • hydrophilic polymers are capable of absorbing more than 10 wt. % of water
  • hygroscopic polymers absorb more than 20 wt. % of water.
  • a "water-swellable" polymer is one that absorbs an amount of water greater than at least 50 wt.% of its own weight, upon immersion in an aqueous medium.
  • crosslinked refers to a composition containing intramolecular and/or intermolecular crosslinks, whether arising through covalent or noncovalent bonding.
  • Noncovalent bonding includes both hydrogen bonding and electrostatic (ionic) bonding.
  • polymer includes linear and branched polymer structures, and also encompasses crosslinked polymers as well as copolymers (which may or may not be crosslinked), thus including block copolymers, alternating copolymers, random copolymers, and the like.
  • oligomers are polymers having a molecular weight below about 1000 Da, preferably below about 800 Da.
  • film-forming hydrophilic polymer refers to a polymer with a plurality of recurring polar groups thereon.
  • the film-forming polymer is present in a higher concentration than each of others composition components, and it is this higher concentration that determines the film-forming characteristics.
  • a film-forming polymer FLP
  • NCC non- covalent crosslinker
  • the NCC presents in the composition in a lower concentration than the FFP, although both polymeric components may belong to the same class of hydrophilic polymers.
  • the ratio between the concentrations of the FFP and NCC determines the density of noncovalent network and entire range of physical properties, including mechanical properties, solubility, swelling and adhesion of the polymer composition.
  • hydrogel is used in the conventional sense to refer to water-swellable polymeric matrices that can absorb a substantial amount of water to form elastic gels, where the "matrices” are three-dimensional networks of macromolecules held together by covalent or non-covalent crosslinks. Upon placement in an aqueous environment, dry hydrogels swell to the extent allowed by the degree of cross-linking. Hydrogels are generally water insoluble, but are able to be partly water soluble, or to dissolve gradually in water soluble.
  • hydrogel composition refers to a composition that either contains a hydrogel or is entirely composed of a hydrogel.
  • hydrogel compositions encompass not only hydrogels per se but also compositions that comprise a hydrogel and one or more non-hydrogel components or compositions.
  • tack and “tacky” are qualitative. However, the terms “substantially nontacky,” “slightly tacky,” and “tacky,” as used herein, may be quantified using the values obtained in a PKI tack determination, a TRBT tack determination, or a PSA tack determination/Polyken Probe (Solutia, Inc.).
  • substantially nontacky is used to refer to a composition having a tack value less than about 25 g-cm/sec
  • lightly tacky refers to a composition having a tack value in the range of about 25 g-cm/sec to about 100 g-cm/sec
  • tacky refers to a composition having a tack value of at least 100 g-cm/sec.
  • plasticizer is used in the conventional sense of the term to refer to a relatively low molecular weight compound that is miscible with a polymer or polymer blend and decreases the glass transition temperature and elastic modulus thereof.
  • PSA pressure sensitive adhesive
  • bioadhesive means a hydrogel that exhibits a pressure-sensitive character of adhesion toward highly hydrated surfaces such as mucosal biological tissue.
  • classical bioadhesives possess no or negligible adhesion towards dry substrates, but become tacky upon absorbance of significant amounts of moisture.
  • targeted (or selective) adhesion towards teeth implies here a strong adhesion towards tooth surface and the lack of any adhesion towards other biological tissues in oral cavity, such as tongue, lips, gingiva, palate, and buccal mucosa.
  • cohesion refers to the intermolecular attraction between like or complementary, self-associating macromolecules.
  • the driving force of an intermolecular cohesion are hydrogen, electrostatic and/or ionic bonding between the complementary macromolecules.
  • the long chain entanglements serve as an additional factor contributing to high cohesive strength.
  • PSA polymers bearing attractive groups
  • interleukin-sensitive Some polymers bearing attractive groups are called “smart”, “intelligent” or “stimuli-sensitive” since they show critical phenomena as, for example, phase transitions that can be induced by external stimuli: changes in temperature, pH, solvent, ionic composition, electric or magnetic fields, light, etc.
  • the PSAs can be considered as “smart” materials because they possess different adhesion towards different substrates.
  • complex or "interpolymer complex” refers to the association of macromolecules of two or more complementary polymers that forms as a result of favorable interactions between their functional groups.
  • Interpolymer complexes are noncovalently crosslinked three-dimensional polymer networks (gels) resulting from ionic, electrostatic or hydrogen bonding between complementary functional groups in their macromolecules. If both complementary polymers contain ionogenic functional groups, their association product is termed polyelectrolyte complex.
  • a distinctive feature of "hydrogen bonding" between proton donating and proton accepting complementary groups is that both the reactive groups and the product of their interaction bear no electric charge.
  • Electrostatic bonding is the interaction of proton donating and proton accepting groups, which are initially uncharged, but their interaction is accompanied with proton transfer and occurrence of the charge.
  • ionic bonding is the interaction of oppositely charged (cationic and anionic) groups with the formation of ionic (salt) bond.
  • interpolymer complexes For the purposes of present invention it is very important that general property of interpolymer complexes is their insolubility in aqueous media, even in that case, when parent polymers are easily soluble. At the same time, usually the interpolymer complexes are capable of gradual swelling in water. In the swollen state they become slowly soluble, fully or partly. The soluble part of the interpolymer complexes is defined as the sol fraction. Insoluble part of the interpolymer complexes is known as the gel fraction.
  • free volume of a polymer is used to define the unoccupied space, or vacancies, available for segmental motion of macromolecules.
  • the free volume of a material is the difference between the bulk volume and the sum of the hard core and vibrational volumes of the constituent building blocks (atoms).
  • the free volume concept has long been used to interpret and explain the molecular mobility of the macromolecules along with such fundamental properties and quantities as the glass transition and glass transition temperature, viscoelastic, adhesion and relaxation behaviors, diffusion, and other transport properties of polymer systems.
  • free volume is a factor controlling the values of cohesive energy density, solubility parameter and the Flory-Huggins interaction parameter.
  • the pressure sensitive bio-adhesive compositions described in present invention can be employed as solid films, hydrogels and liquid solutions.
  • the adhesive films can be either gradually soluble in saliva in the course of their application to teeth, or insoluble. Insoluble films should be removed from the teeth and are defined further as strips.
  • compositions should be applicable to teeth either in the form of viscous gel or as tooth whitening one-layer transparent or translucent strip.
  • thermodynamic model of adhesion generally attributed to Sharpe and
  • HA hydroxylapatite
  • the HA is a naturally occurring mineral form of calcium apatite with the formula Ca 5 (P0 4 ) 3 (OH), but is usually written Ca 10 (PO 4 ) 6 (OH) 2 to denote that the crystal unit cell comprises two entities.
  • the Orf ion in the HA can be replaced by fluoride, chloride or carbonate anions, producing fluorapatite (FA), chlorapatite (ChA) or carbonate apatite (CA).
  • the contents of HA, FA, ChA and CA in tooth enamel are 75, 0.66, 4.4 and 19 %, respectively.
  • the presence of the hydroxyl ions in the enamel implies that the most strong specific (ionic) interfacial bonds with tooth surface, and, consequently, carboxyl containing polymers (i.e. polyacids) will provide adhesion towards dental enamel.
  • Polyacids suitable for their application in dental adhesives include poly(acrylic acid), poly(methacrylic acid), poly(maleic acid), corresponding copolymers and blends therof.
  • Other suitable carboxyl-containing polymers are hyaluronic acid, alginic acid and cellulose derivatives listed below.
  • Mineral salts are high surface energy materials, forming stronger adhesive bonds with polar (hydrophilic) polymers which possess high surface energy.
  • suitable proton-donating polymers utilized as the basis for dental adhesives also include polyalcohols, polyphenols, and hydroxyl-containing cellulose derivatives, e.g. poly(vinyl alcohol), poly(vinyl phenol), hydroxyalkyl cellulose.
  • adhesion to teeth can be also provided by proton-accepting polymers (polybases), e.g. poly(acryl amides), polyvinyl amides), poly(vinyl lactams), aminogroup-containing acrylates, methacrylates, poly(vinyl amine) and chitosan.
  • polybases e.g. poly(acryl amides), polyvinyl amides), poly(vinyl lactams), aminogroup-containing acrylates, methacrylates, poly(vinyl amine) and chitosan.
  • the term "mucoadhesion" was coined for the adhesion of the polymers with the surface of the mucosal layer.
  • the mucosal layer is made up of mucus which is secreted by the goblet cells (glandular columnar epithelial cells) and is a viscoelastic fluid. It lines the visceral organs, which are exposed to the external environment.
  • the main components constituting the mucosa include water and mucin (an anionic polyelectrolyte), while the other components include proteins, lipids and mucopolysaccharides. Water and mucin constitute > 99% of the total composition of the mucus and out of this > 95% is water.
  • the gel-like structure of the mucus can be attributed to the intermolecular entanglements of the mucin glycoproteins along with the non-covalent interactions (e.g. hydrogen, electrostatic and hydrophobic bonds) which results in the formation of a hydrated gel-like structure and explains the viscoelastic nature of the mucus (S. Roy, K. Pal, A. Anis, K. Pramanik, B.Prabhakar, Polymers in Mucoadhesive Drug Delivery System: A Brief Note, Designed Monomers and Polymers 2009, 12, 483 - 495).
  • non-covalent interactions e.g. hydrogen, electrostatic and hydrophobic bonds
  • the various mucoadhesive polymers used for the development of buccal drug delivery systems include cyanoacrylates, polyacrylic acid, sodium carboxymethylcellulose, hyaluronic acid, hydroxypropylcellulose, polycarbophil, chitosan and gellan.
  • PAA poly(acrylic acid)
  • hydroxypropyl methylcellulose and poly(methylacrylate) derivatives
  • naturally occurring polymers such as hyaluronic acid and chitosan.
  • PAA has been considered as a good mucoadhesive.
  • PAA due to a high glass transition temperature and higher interfacial free energy, PAA does not wet the mucosal surface to the optimal level, causing loose interpenetration and interdiffusion of the polymer.
  • PAA is copolymerised with polyethylene glycol (PEG) or poly(vinyl pyrrolidone) (PVP) to improve these properties
  • PEG polyethylene glycol
  • PVP poly(vinyl pyrrolidone)
  • Equation (1) where k is a constant taking into account interfacial adhesive - substrate interaction, b and / are the width and thickness of adhesive layer, N is the number of segments of size a in the polymer chain, D is the self diffusion coefficient of the polymer segment, r is the PSA relaxation time, k H is Boltzmann's constant, T is temperature (K), and ⁇ 3 ⁇ 4 is the ultimate tensile stress of PSA film under uniaxial stretching up to break (see M.M.
  • Equation (1) the high adhesive strength of PSA polymer is the result of compromise between two mutually conflicting properties, the high molecular mobility controlled by large free volume, and the strong intermolecular cohesion energy, governing the PSA cohesive strength.
  • the targeted "smart" polymer adhesion to dental enamel in oral cavity results from the dissimilarity in mechanical properties of the substrates.
  • High adhesion requires the formation of good adhesive contact that can be achieved between soft adhesive and rigid substrate.
  • the adhesive is harder than the substrate, the good adhesive contact and the high adhesion are unattainable.
  • Teeth are the rigid substrate, whereas tongue, gums and other mucosal tissues are the soft substrates. In this way, the hardness of different tissues in oral cavity provides a major tool by means of which the "smart" bio-PSA in the mouth recognizes its target substrate.
  • the complex melting occurs in the range of 88 - 92 °C, and the decomposition proceeds at the temperature above 115 0 C.
  • thermodesorption of the hydrogen peroxide takes a place above 74 0 C, and the decomposition occurs above 142 0 C.
  • the carboxyl containing polymer should be first mixed with a complementary stabilizer of the hydrogen peroxide to interlock the carboxyl protons by hydrogen bonding and the whitening agent has to be added last.
  • Suitable hydrogen peroxide stabilizers in this case are proton accepting polymers and low molecular weight compounds, which include, without any limitation, homo- and copolymers of N-vinyl lactams, acrylamides, polyurethanes, polyurea, polypeptides, and the low molecular weight urea.
  • tooth whitening compositions of the invention a single whitening agent can be employed or the combination thereof.
  • a tooth whitening formulation in a first embodiment, comprises a first tooth whitening agent that is inert in a dry environment but activated in the presence of moisture to release peroxide and produce an alkaline pH, a second tooth whitening agent that releases peroxide rapidly upon contact with moisture in the presence of base, and at least one water-swellable, water-insoluble polymer.
  • the first tooth whitening agent may be, for example, an addition compound of (a) a salt of an oxyanion and (b) hydrogen peroxide.
  • Such tooth whitening agents include, without limitation, sodium percarbonate (2Na 2 C0 3 3H 2 0 2 ; also known as sodium carbonate peroxyhydrate and peroxy sodium carbonate), which breaks down to sodium carbonate and hydrogen peroxide in water, with a resultant increase in the pH of the solution.
  • Such tooth whitening agents also include sodium perborate (NaB0 3 ), sodium perborate monohydrate, and sodium perborate tetrahydrate.
  • the second tooth whitening agent may be, for example, carbamide peroxide (CO(NH 2 ) 2 -H 2 0 2 ; also known as urea peroxide, Urea peroxide (Percarbamide); Hydrogen peroxide compounded with urea (1:1); Hydroperit; Hyperol; Ortizon; Perhydrit; Perhydrol-urea; Thenardol; Urea compounded with hydrogen peroxide (1:1); Urea Hydroperoxide), or selected from any number of other organic and inorganic compounds that release peroxide rapidly in the presence of aqueous base.
  • carbamide peroxide CO(NH 2 ) 2 -H 2 0 2
  • Percarbamide also known as urea peroxide, Urea peroxide (Percarbamide)
  • the water-swellable, water-insoluble polymer is capable of at least some degree of swelling when immersed in an aqueous liquid but is either completely insoluble in water or water-insoluble within a selected pH range, generally up to a pH of at least about 7.5 to 8.5.
  • the polymer may be comprised of a cellulose ester, for example, cellulose acetate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP), cellulose butyrate (CB), cellulose propionate butyrate (CPB), cellulose diacetate (CDA), cellulose triacetate (CTA), or the like.
  • a cellulose ester for example, cellulose acetate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP), cellulose butyrate (CB), cellulose propionate butyrate (CPB), cellulose diacetate (CDA), cellulose triacetate (CTA
  • cellulose esters suitable herein include CA 320, CA 398, CAB 381, CAB 551 , CAB 553, CAP 482, CAP 504, all available from Eastman Chemical Company, Kingsport, Tenn. Such cellulose esters typically have a number average molecular weight of between about 10,000 and about 75,000.
  • cellulose esters comprise a mixture of cellulose and cellulose ester monomer units; for example, commercially available cellulose acetate butyrate contains cellulose acetate monomer units as well as cellulose butyrate monomer units and unesterified cellulose units.
  • Preferred cellulose esters herein are cellulose acetate butyrate compositions and cellulose acetate propionate compositions with the following properties: cellulose acetate butyrate, butyrate content 17-52%, acetyl content 2.0-29.5%, unesterified hydroxyl content, 1.1 -4.8%, molecular weight 12,000-20,000 g/mole, glass transition temperature T g in the range of 96-141°C, and melting temperature in the range of 130-240°C; and cellulose acetate propionate, propionate content 42.5-47.7%, acetyl content 0.6-1.5%, unesterified hydroxyl content, 1.7-5.0%, molecular weight 15,000- 75,000 g/mole, glass transition temperature T g in the range of 142-159°C, and melting temperature in the range of 188-210°C.
  • Suitable cellulosic polymers typically have an inherent viscosity (I. V.) of about 0.2 to about 3.0 deciliters/gram, preferably about 1 to about 1.6 deciliters/gram, as measured at a temperature of 25°C for a 0.5 gram sample in 100 ml of a 60/40 by weight solution of phenol/tetrachloroethane.
  • I. V. inherent viscosity
  • acrylate polymers generally formed from acrylic acid, methacrylic acid, acrylate, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate, a dialkylaminoalkyl acrylate, a dialkylaminoalkyl methacrylate, a trialkylammonioalkyl acrylate, and/or a trialkylammonioalkyl methacrylate.
  • Preferred such polymers are copolymers of acrylic acid, methacrylic acid, methyl methacrylate, ethyl methacrylate, 2-dimethylaminoethyl methacrylate, and/or trimethylammonioethyl methacrylate chloride.
  • Suitable acrylate polymers are those copolymers available under the tradename
  • Eudragit from Rohm Pharma (Germany),, now «Evonik Industries »
  • the Eudragit series E, L, S, RL, RS and NE copolymers are available as solubilized in organic solvent, in an aqueous dispersion, or as a dry powder.
  • Preferred acrylate polymers are copolymers of methacrylic acid and methyl methacrylate, such as the Eudragit L and Eudragit S series polymers.
  • Particularly preferred such copolymers are Eudragit L-30D-55 and Eudragit L- 100-55 (the latter copolymer is a spray-dried form of Eudragit L-30D-55 that can be reconstituted with water).
  • the molecular weight of the Eudragit L-30D-55 and Eudragit L-100-55 copolymer is approximately 135,000 Da, with a ratio of free carboxyl groups to ester groups of approximately 1 :1.
  • the copolymer is generally insoluble in aqueous fluids having a pH below 5.5.
  • Another particularly suitable methacrylic acid-methyl methacrylate copolymer is Eudragit S-100, which differs from Eudragit L-30D-55 in that the ratio of free carboxyl groups to ester groups is approximately 1 :2.
  • Eudragit S-100 is insoluble at pH below 5.5, but unlike Eudragit L-30D-55, is poorly soluble in aqueous fluids having a pH in the range of 5.5 to 7.0.
  • This copolymer is soluble at pH 7.0 and above.
  • Eudragit L-100 may also be used, which has a pH-dependent solubility profile between that of Eudragit L-30D-55 and Eudragit S-100, insofar as it is insoluble at a pH below 6.0. It will be appreciated by those skilled in the art that Eudragit L-30D-55, L- 100-55, L-100, and S-100 can be replaced with other acceptable polymers having similar pH-dependent solubility characteristics.
  • acrylate polymers are cationic, such as the Eudragit E, RS, and RL series polymers.
  • Eudragit EIOO and E PO are cationic copolymers of dimethylaminoethyl methacrylate and neutral methacrylates (e.g., methyl methacrylate), while Eudragit RS and Eudragit RL polymers are analogous polymers, composed of neutral methacrylic acid esters and a small proportion of trimethylammonioethyl methacrylate.
  • the formulation may contain a single water-swellable, water-insoluble polymer as described above. Alternatively, an admixture of at least two water-swellable, water-insoluble polymers may be present.
  • an exemplary formulation is provided by combining a cationic water-swellable, water- insoluble polymer with an anionic water swellable, water-insoluble polymer, such that the polymers are ionically associated with each other and form a polymer matrix.
  • the cationic polymer may be an acrylate-based polymer with pendant quaternary ammonium groups or tertiary amino groups (as exemplified by a Eudragit RS , Eudragit RL, Eudragit E copolymer), and the anionic polymer may be an ionized acrylic acid or methacrylic acid polymer such as a Eudragit L or Eudragit S copolymer.
  • the anionic polymer may also be, for example, hydroxypropyl methylcellulose phthalate.
  • the tooth whitening formulation will generally include a crosslinked hydrophilic polymer as well.
  • the crosslinked hydrophilic polymer may be covalently crosslinked, ionically crosslinked, or crosslinked via hydrogen bonding, wherein crosslinking may be either intramolecular or intermolecular, and the formulations may contain any combinations of such crosslinked polymers.
  • the hydrophilic polymer may be crosslinked via a crosslinking agent, e.g., via a low molecular weight complementary oligomer.
  • Suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer.
  • Such polymers include, by way of example, poly(N-vinyl lactams), poly(N-vinyl acrylamides), poly(N-alkylacrylamides), substituted and unsubstituted acrylic and methacrylic acid polymers, polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof and copolymers with other types of hydrophilic monomers (e.g. vinyl acetate).
  • hydrophilic polymers include, but are not limited to: polysaccharides; crosslinked acrylate polymers and copolymers; carbomers, i.e., hydroxylated vinylic polymers (also referred to as "interpolymers") which are prepared by crosslinking a monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose (commercially available under the trademark Carbopol ® from the B. F. Goodrich Chemical Company); crosslinked acrylamide-sodium acrylate copolymers; gelatin; vegetable polysaccharides, such as alginates, pectins, carrageenans, or xanthan; starch and starch derivatives; and galactomannan and galactomannan derivatives.
  • polysaccharides such as alginates, pectins, carrageenans, or xanthan
  • starch and starch derivatives such as alginates, pectins, carrageenans, or xanthan
  • Polysaccharide materials include, for instance, crosslinked, normally water- soluble cellulose derivatives that are crosslinked to provide water-insoluble, water- swellable compounds, such as crosslinked sodium carboxymethylcellulose (CMC), crosslinked hydroxyethyl cellulose (HEC), crosslinked partial free acid CMC, and guar gum grafted with acrylamide and acrylic acid salts in combination with divinyl compounds, e.g., methylene-bis acrylamide.
  • CMC carboxymethylcellulose
  • HEC crosslinked hydroxyethyl cellulose
  • guar gum grafted with acrylamide and acrylic acid salts in combination with divinyl compounds e.g., methylene-bis acrylamide.
  • the more preferred materials are crosslinked CMC derivatives, particularly crosslinked sodium CMC and crosslinked HEC.
  • Other polysaccharides suitable herein include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), and the like
  • Poly(N-vinyl lactams) useful herein are preferably homopolymers or copolymers of N-vinyl lactam monomer units, with N-vinyl lactam monomer units representing the majority of the total monomeric units of a poly(N-vinyl lactams) copolymer.
  • Preferred poly(N-vinyl lactams) for use in conjunction with the invention are prepared by polymerization of one or more of the following N-vinyl lactam monomers: N-vinyl-2- pyrrolidone; N-vinyl-2-valerolactam; and N-vinyl-2-caprolactam.
  • Nonlimiting examples of non-N-vinyl lactam comonomers useful for copolymerzation with N-vinyl lactam monomeric units include ⁇ , ⁇ -dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethylmethacrylate, acrylamide, 2-acrylamido-2-methyl-l -propane sulfonic acid or its salt, and vinyl acetate.
  • Poly (N-alkylacrylamides) include, by way of example, poly(methacrylamide) and poly(N-isopropyl acrylamide) (PNIPAM).
  • Polymers of carboxy vinyl monomers are typically formed from acrylic acid, methacrylic acid, crotonic acid, isocrotonic acid, itaconic acid and anhydride, a 1,2-dicarboxylic acid such as maleic acid or fumaric acid, maleic anhydride, or mixtures thereof, with preferred hydrophilic polymers within this class including polyacrylic acid and polymethacrylic acid, with polyacrylic acid most preferred.
  • Preferred hydrophilic polymers herein are the following: poly(N-vinyl lactams), particularly polyvinyl pyrrolidone (PVP) and poly(N-vinyl caprolactam) (PVCap); poly(N-vinyl acetamides), particularly polyacetamide per se; polymers of carboxy vinyl monomers, particularly polyacrylic acid and polymethacrylic acid; and copolymers and blends thereof. PVP and PVCap are particularly preferred.
  • the molecular weight of the hydrophilic polymer is not critical; however, the number average molecular weight of the hydrophilic polymer is generally in the range of approximately 20,000 to 2,000,000, more typically in the range of approximately 200,000 to 1 ,000,000.
  • Covalent crosslinking may be accomplished in several ways. For instance, the hydrophilic polymer, or the hydrophilic polymer and a complementary oligomer, may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent.
  • Covalently crosslinked hydrophilic polymers may also be obtained commercially, for example, crosslinked sodium CMC is available under the tradename Aquasorb® (e.g., Aquasorb ® A500) from Aqualon, a division of Hercules, Inc., and crosslinked PVP is available under the tradename Kollidon ® (e.g., Kollidon ® CL, and Kollidon ® CL-M, a micronized form of crosslinked PVP, both available from BASF).
  • Aquasorb® e.g., Aquasorb ® A500
  • PVP is available under the tradename Kollidon ® (e.g., Kollidon ® CL, and Kollidon ® CL-M, a micronized form of crosslinked PVP, both available from BASF).
  • a free radical polymerization initiator is used, and can be any of the known free radical-generating initiators conventionally used in vinyl polymerization.
  • Preferred initiators are organic peroxides and azo compounds, generally used in an amount from about 0.01 wt.% to 15 wt.%, preferably 0.05 wt.% to 10 wt.%, more preferably from about 0.1 wt.% to about 5% and most preferably from about 0.5 wt.% to about 4 wt.% of the polymerizable material.
  • Suitable organic peroxides include dialkyl peroxides such as t-butyl peroxide and 2,2 bis(f-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as ?-butyl perbenzoate and /-butyl per-2-ethylhexanoate, perdi carbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methyl ethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert-butyl ⁇ hydroperoxide.
  • dialkyl peroxides such as t-butyl peroxide and 2,2 bis(f-butylperoxy)propane
  • diacyl peroxides such as benzoyl peroxide and acet
  • Suitable azo compounds include azo bis (isobutyronitrile) and azo bis (2,4-dimethylvaleronitrile).
  • the temperature for thermal crosslinking will depend on the actual components and may be readily determined by one of ordinary skill in the art, but typically ranges from about 80 °C to about 200 °C.
  • Crosslinking may also be accomplished with radiation, typically in the presence of a photoinitator.
  • the radiation may be ultraviolet, alpha, beta, gamma, electron beam, and x-ray radiation, although ultraviolet radiation is preferred.
  • Useful photosensitizers are triplet sensitizers of the "hydrogen abstraction" type, and include benzophenone and substituted benzophenone and acetophenones such as benzyl dimethyl ketal, 4- acryloxybenzophenone (ABP), 1 -hydroxy-cyclohexyl phenyl ketone, 2,2- diethoxyacetophenone and 2,2-dimethoxy-2-phenylaceto-phenone, substituted alpha- ketols such as 2-methyl-2-hydroxypropiophenone, benzoin ethers such as benzoin methyl ether and benzoin isopropyl ether, substituted benzoin ethers such as anisoin methyl ether, aromatic sulfonyl chlorides such as 2-naphthal
  • photosensitizers of the hydrogen abstraction type higher intensity UV exposure may be necessary to achieve sufficient crosslinking.
  • Such exposure can be provided by a mercury lamp processor such as those available from PPG, Fusion, Xenon, and others.
  • Crosslinking may also be induced by irradiating with gamma radiation or an electron beam. Appropriate irradiation parameters, i.e., the type and dose of radiation used to effect crosslinking, will be apparent to those skilled in the art.
  • Suitable chemical curing agents also referred to as chemical cross-linking "promoters,” include, without limitation, polymercaptans such as 2,2-dimercapto diethylether, dipentaerythritol hexa(3-mercaptopropionate), ethylene bis(3- mercaptoacetate), pentaerythritol tetra(3-mercapto propionate), pentaerythritol tetrathioglycolate, polyethylene glycol dimercaptoacetate, polyethylene glycol di(3- mercaptopropionate), trimethylolethane tri(3-mercaptopropionate), trimethylolethane trithioglycolate, trimethylolpropane tri(3-mercapto-propionate), trimethylolpropane trithioglycolate, dithioethane, di- or trithiopropane and 1 ,6-hexane dithiol.
  • the crosslinked hydrophilic polymer may also comprise a blend of a hydrophilic polymer and a low molecular weight complementary oligomer capable of crosslinking the polymer via hydrogen bonding.
  • the hydrophilic polymer may or may not be crosslinked prior to admixture with the complementary oligomer. If the hydrophilic polymer is crosslinked prior to admixture with the complementary oligomer, it may be preferred to synthesize the polymer in crosslinked form, by admixing a monomelic precursor to the polymer with multifunctional comonomer and copolymerizing.
  • Examples of monomelic precursors and corresponding polymeric products are as follows: N-vinyl amide precursors for a poly(N-vinyl amide) product; N-alkylacrylamides for a poly(N- alkylacrylamide) product; acrylic acid for a polyacrylic acid product; methacrylic acid for a polymethacrylic acid product; acrylonitrile for a poly(acrylonitrile) product; and N- vinyl pyrrolidone (NVP) for a poly(vinylpyrrolidone) (PVP) product.
  • Polymerization may be carried out in bulk, in suspension, in solution, or in an emulsion.
  • Solution polymerization is preferred, and polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred.
  • polar organic solvents such as ethyl acetate and lower alkanols (e.g., ethanol, isopropyl alcohol, etc.) are particularly preferred.
  • synthesis will typically take place via a free radical polymerization process in the presence of a free radical initiator as described above.
  • the multifunctional comonomer include, for example, bisacrylamide, acrylic or methacrylic esters of diols such as butanediol and hexanediol (1,6-hexane diol diacrylate is preferred), other acrylates such as pentaerythritol tetraacrylate, and 1,2-ethylene glycol diacrylate, and 1 ,12-dodecanediol diacrylate.
  • multifunctional crosslinking monomers include oligomeric and polymeric multifunctional (meth)acrylates, e.g., poly(ethylene oxide) diacrylate or poly(ethylene oxide) dimethacrylate; polyvinylic crosslinking agents such as substituted and unsubstituted divinylbenzene; and difunctional urethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (1500 weight average molecular weight and 5000 weight average molecular weight acrylated urethanes, respectively— both available from UCB of Smyrna, Ga.), and combinations thereof.
  • oligomeric and polymeric multifunctional (meth)acrylates e.g., poly(ethylene oxide) diacrylate or poly(ethylene oxide) dimethacrylate
  • polyvinylic crosslinking agents such as substituted and unsubstituted divinylbenzene
  • difunctional urethane acrylates such as EBECRYL® 270 and EBECRYL® 230 (1500
  • the amount used will preferably be such that the weight ratio of crosslinking agent to hydrophilic polymer is in the range of about 1 : 100 to 1 :5.
  • chemical crosslinking is combined with radiation curing.
  • the crosslinked hydrophilic polymer is in the form of a blend of a hydrophilic polymer and a low molecular weight complementary oligomer
  • the blend will usually provide a matrix that is crosslinked solely by hydrogen bonds formed between the termini of the oligomer and pendant groups on the hydrophilic polymer.
  • suitable hydrophilic polymers include repeating units derived from an N-vinyl lactam monomer, a carboxy vinyl monomer, a vinyl ester monomer, an ester of a carboxy vinyl monomer, a vinyl amide monomer, and/or a hydroxy vinyl monomer, as described above with regard to crosslinked hydrophilic polymers per se, and preferred hydrophilic polymers in this blend are also as described above for those polymers.
  • the oligomer is generally "complementary" to the hydrophilic polymers in that it is capable of hydrogen bonding thereto.
  • the complementary oligomer is terminated with hydroxyl groups, amino or carboxyl groups.
  • the oligomer typically has a glass transition temperature T g in the range of about -100°C to about -30°C and a melting temperature T m lower than about 20°C.
  • the oligomer may be also amorphous.
  • the difference between the T g values the hydrophilic polymer and the oligomer is preferably greater than about 50 °C, more preferably greater than about 100 °C, and most preferably in the range of about 150°C to about 300°C.
  • the hydrophilic polymer and complementary oligomer should be compatible, i.e. capable of forming a homogeneous blend that exhibits a single T g , intermediate between those of the unblended components.
  • the oligomer will have a molecular weight in the range from about 45 to about 800, preferably in the range of about 45 to about 600.
  • suitable oligomers include, but are not limited to, low molecular weight polyalcohols (e.g.
  • glycerol oligoalkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (e.g., glycol ethers), alkane diols from butane diol to octane diol, and carboxyl -terminated and amino-terminated derivatives of polyalkylene glycols.
  • ether alcohols e.g., glycol ethers
  • alkane diols from butane diol to octane diol e.g., glycol ethers
  • carboxyl -terminated and amino-terminated derivatives of polyalkylene glycols e.g., polyalkylene glycols, optionally carboxyl-terminated, are preferred herein, and polyethylene glycol having a molecular weight in the range of about 300 to 600 is an optimal complementary oligomer.
  • the hydrophilic polymer and the complementary oligomer should be miscible with respect to each other and have disparate chain lengths (as may be deduced from the above).
  • the ratio of the average molecular weight of the hydrophilic polymer to that of the oligomer should be within about 200 and 200,000, preferably within about 1 ,250 and 20,000.
  • the polymer and the oligomer should contain complementary functional groups capable of hydrogen bonding, ionically bonding, or covalently bonding to each other.
  • the complementary functional groups of the polymer are located throughout the polymeric chains, while the functional groups of the oligomer are preferably located at the two termini of a linear molecule, and are not present along the backbone. Forming hydrogen bonds or ionic bonds between the two terminal functional groups of the oligomer and the corresponding functional groups contained along the backbone of the hydrophilic polymer results in a noncovalently linked supramolecular network.
  • the ratio of the hydrophilic polymer to the complementary oligomer in the aforementioned blend affects both adhesive strength and cohesive strength.
  • the complementary oligomer decreases the glass transition of the hydrophilic polymer/complementary oligomer blend to a greater degree than predicted by the Fox equation, which is given by equation (2) 1
  • T g predicted is the predicted glass transition temperature of the hydrophilic polymer/complementary oligomer blend
  • w po i is the weight fraction of the hydrophilic polymer in the blend
  • w p ⁇ is the weight fraction of the complementary oligomer in the blend
  • T g po i is the glass transition temperature of the hydrophilic polymer
  • T gpt is the glass transition temperature of the complementary oligomer.
  • an adhesive composition having optimized adhesive and cohesive strength can be prepared from a hydrophilic polymer and a complementary oligomer by selecting the components and their relative amounts to give a predetermined deviation from T g pre icted - Generally, to maximize .adhesion, the predetermined deviation from T g predicted will be the maximum negative deviation, while to minimize adhesion, any negative deviation from T g predicted is minimized.
  • the complementary oligomer represents approximately 25 wt.% to 75 wt.
  • the hydrophilic polymer represents approximately 75 wt.% to 25 wt.%, preferably about 70 wt.% to about 40 wt.%, of the hydrophilic polymer/oligomer blend.
  • the hydrophilic polymer, and optionally the complementary oligomer should be covalently crosslinked.
  • the hydrophilic polymer may be covalently crosslinked, either intramolecularly or intermolecularly, and/or the hydrophilic polymer and the complementary oligomer may be covalently crosslinked. In the former case, there are no covalent bonds linking the hydrophilic polymer to the complementary oligomer, while in the latter case, there are covalent crosslinks binding the hydrophilic polymer to the complementary oligomer.
  • the hydrophilic polymer, or the hydrophilic polymer and the complementary oligomer may be covalently crosslinked using heat, radiation, or a chemical curing (crosslinking) agent. The degree of crosslinking should be sufficient to eliminate or at least minimize cold flow under compression.
  • the oligomer should be terminated at each end with a group capable of undergoing reaction with a functional group on the hydrophilic polymer.
  • a functional group on the hydrophilic polymer include, for example, hydroxyl groups, amino groups, and carboxyl groups.
  • Suitable low molecular weight plasticizers include: dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates, and mixed alkyl-aryl phthalates, as represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di(2-ethylhexyl)-phthalate, di-isopropyl phthalate, diamyl phthalate and dicapryl phthalate; alkyl and aryl phosphates such as tributyl phosphate, trioctyl phosphate, tricresyl phosphate, and triphenyl phosphate; alkyl citrate and citrate esters such as trimethyl citrate, triethyl citrate, tributyl citrate, acetyl trieth
  • compositions of the invention are readily controlled by adjusting one or more parameters during formulation.
  • the adhesiveness of the composition can be controlled during manufacture in order to increase or decrease the degree to which the composition will adhere to the teeth in the presence of moisture. This can be accomplished by varying type and/or amount of different components, or by changing the mode of manufacture.
  • compositions prepared using a conventional melt extrusion process are generally, although not necessarily, somewhat less tacky than compositions prepared using a solution cast technique.
  • adhesive hydrogel is softer than such rigid substrate as tooth, under slight external pressure provided by touch with finger it behaves like a liquid, spreading onto teeth surface and forming perfect adhesive contact.
  • Covalent or noncovalent crosslinked structure of the adhesive hydrogel offers elasticity and enhances the resistance to detaching force, rendering the strength of adhesive joint with dental surface.
  • the dental adhesive in the swollen state is harder than mucosal membranes, it does not fit to oral mucosa and forms poor adhesive contact.
  • the adhesive hydrogel demonstrates no adhesion towards tongue, gingivae, inner cheek surface and palate.
  • the "smart" adhesive hydrogel should manifest strictly specified softness, evaluated in terms of dynamic elasticity modulus, G', and loss tangent, tan ⁇ .
  • G' dynamic elasticity modulus
  • loss tangent is within the range from 0.60 to 1.20.
  • cohesion energy free volume ratio
  • the adhesive hydrogel In the swollen state the adhesive hydrogel should possess the Tg values ranged between -10 and -130 °C.
  • a tooth whitening composition is provided that is composed of an admixture of a tooth whitening agent, generally, although not necessarily, one that is inert in a dry environment but activated in the presence of moisture, and at least two water-swellable, water-insoluble polymers, wherein a first water-swellable, water-insoluble polymer is cationic, a second water-swellable, water-insoluble polymer is anionic, and the polymers are ionically associated with each other to form a polymer matrix.
  • the composition may contain a single tooth whitening agent, but necessarily includes a mixture of ionically associated polymers as are present in the preferred embodiment discussed above.
  • the cationic polymer may be, for example, an acrylate-based polymer with pendant quaternary ammonium groups, and the anionic polymer may be an ionized acrylic acid or methacrylic acid polymer. Specific such polymers are as described earlier herein.
  • a tooth whitening composition is provided that is composed of an admixture of: 1.5 wt.% to 30 wt. , preferably 1.5 wt.% to 20 wt.%, more preferably 1.5 wt.% to 90 wt.%, and most preferably 1.5 wt.% to 95 wt.%, of a hydrophilic polymer composition composed of (a) a covalently crosslinked hydrophilic polymer, and/or (b) a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding thereto; 40 wt.% to 90 wt.%, preferably 45 wt.
  • suitable tooth whitening agents include peroxides, metal chlorites (e.g., calcium chlorite and sodium chlorite), perborates (e.g., sodium perborate), percarbonates (e.g., sodium percarbonate), peroxyacids (e.g., diperoxydodecanoic acid), and combinations thereof.
  • metal chlorites e.g., calcium chlorite and sodium chlorite
  • perborates e.g., sodium perborate
  • percarbonates e.g., sodium percarbonate
  • peroxyacids e.g., diperoxydodecanoic acid
  • Peroxides are preferred; representative peroxides include hydrogen peroxide, calcium peroxide, carbamide peroxide, dialkyl peroxides such as /- butyl peroxide and 2,2 bis(/-butylperoxy)propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as /-butyl perbenzoate and /-butyl per-2- ethylhexanoate, perdicarbonates such as dicetyl peroxy dicarbonate and dicyclohexyl peroxy dicarbonate, ketone peroxides such as cyclohexanone peroxide and methylethylketone peroxide, and hydroperoxides such as cumene hydroperoxide and tert- butyl hydroperoxide.
  • representative peroxides include hydrogen peroxide, calcium peroxide, carbamide peroxide, dialkyl peroxides such as /- buty
  • the tooth whitening compositions of the invention may include any of a number of optional additives, such as anti-tartar agents, enzymes, flavoring agents, sweeteners, fillers, preservatives, and breath fresheners.
  • optional additives such as anti-tartar agents, enzymes, flavoring agents, sweeteners, fillers, preservatives, and breath fresheners.
  • Anti-tartar agents include phosphates such as pyrophosphates, polyphosphates, polyphosphonates (e.g., ethane- 1 -hydroxy- 1 ,1-diphosphonate, 1-azacycloheptane-l ,1- diphosphonate, and linear alkyl diphosphonates), and salts thereof; linear carboxylic acids; and sodium zinc citrate; and mixtures thereof.
  • phosphates such as pyrophosphates, polyphosphates, polyphosphonates (e.g., ethane- 1 -hydroxy- 1 ,1-diphosphonate, 1-azacycloheptane-l ,1- diphosphonate, and linear alkyl diphosphonates), and salts thereof; linear carboxylic acids; and sodium zinc citrate; and mixtures thereof.
  • Preferred pyrophosphate salts are the alkali metal pyrophosphate salts and the hydrated or unhydrated forms of disodium dihydrogen pyrophosphate (Na 2 H 2 P 2 0 7 ), tetrasodium pyrophosphate (Na 4 P 2 0 7 ), and tetrapotassium pyrophosphate ( ⁇ ⁇ 2 0 7 ).
  • Anti-tartar agents also include betaines and amine oxides, as described in U.S. Patent No. 6,315,991 to Zofchak.
  • Enzymes useful in inhibiting the formation of plaque, calculus, or dental caries are also useful in the compositions.
  • Such enzymes include: proteases that break down salivary proteins which are absorbed onto the tooth surface and form the pellicle, or first layer of plaque; lipases which destroy bacteria by lysing proteins and lipids which form the structural component of bacterial cell walls and membranes; dextranases, glucanohydrolases, endoglycosidases, and mucinases which break down the bacterial skeletal structure which forms a matrix for bacterial adhesion to the tooth; and amylases which prevent the development of calculus by breaking-up the carbohydrate- protein complex that binds calcium.
  • Preferred enzymes include any of the commercially available proteases; dextranases; glucanohydrolases; endoglycosidases; amylases; mutanases; lipases; mucinases; and compatible mixtures thereof.
  • flavorants include wintergreen, peppermint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavor oils, and oleoresins, as known in the art, as well as combinations thereof.
  • the amount of flavorant employed is normally a matter of preference, subject to such factors as flavor type, individual flavor, and strength desired.
  • the composition comprises from about 0.1 wt% to about 5 wt% flavorant.
  • Sweeteners useful in the present compositions include sucrose, fructose, aspartame, xylitol and saccharine.
  • compositions may also contain active agents for treating adverse conditions of the teeth and surrounding tissue, e.g., periodontal and oral infections, periodontal lesions, dental caries or decay, and gingivitis.
  • the active agent can be, for example, a nonsteroidal anti-inflammatory/analgesic, a steroidal anti-inflammatory agents, a local anesthetic agent, a bactericidal agent, an antibiotic, an antifungal agent, or a tooth desensitizing agent. See, e.g., U.S. Patent Publication Ns. US 2003/0152528 Al to Singh et al., published August 14, 2003, the disclosure of which is incorporated by reference herein.
  • the tooth whitening compositions of the invention can be applied to the teeth in any suitable manner, although it is preferred that the compositions be present as a flexible film that is applied across a row of teeth as a "tooth whitening strip.”
  • a thin hydrophobic erodible backing layer may be used on the outer surface of tooth whitening strip which is comprised of a polymer composition that erodes in a moist environment at a same or slower rate than the hydrogel and is substantially impermeable for hydrogen peroxide.
  • a polymer composition that erodes in a moist environment at a same or slower rate than the hydrogel and is substantially impermeable for hydrogen peroxide.
  • the backing member include, by way of example, and not limitation, polyolefins, polyesters, fluoropolymers and hydrophobic alkylacrylate polymers. Combinations, i.e., blends of any of these different polymers can also serve as backing member material.
  • the hydrogel erodes in about 30 minutes to 24 hours after placement in a moist environment, and in another embodiment the hydrogel erodes about 30 minutes to 8 hours after placement.
  • the erodible backing member in one embodiment, erodes about 30 minutes to 24 hours after the hydrogel has eroded, while in another embodiment the backing erodes within about 3 hours after hydrogel has eroded.
  • the erodible backing member material can be selected so as to erode at a slightly slower or approximately the same rate (e.g., when they both erode within about 24 hours), but is preferably selected so that it erodes at a slower rate than the hydrogel composition, when in use.
  • the erodible backing member erodes at least about 200% slower than the hydrogel, in another embodiment, the backing erodes at least about 100% slower, in a different embodiment the backing erodes at least about 50% slower, and in yet another embodiment the backing erodes at least about 5% slower than the hydrogel.
  • tooth whitening strip of present invention contains no backing film that is insoluble in saliva, it can be used as tooth whitening film for night application. Gradual solubility of the film in saliva obviates a danger of user's choking by the film during a sleep.
  • the tooth whitening compositions of the invention are used by removing the product from its package, typically a moisture-free sealed pouch, removing the release liner, and applying the adhesive layer to the teeth.
  • the tooth whitening systems described herein can be provided in a variety of sizes, so that the composition can be applied to the entirety or any portion of a tooth, and to any number of teeth at one time.
  • the system can be left in place for an extended period of time, typically in the range of about 10 minutes to 8 hours, preferably in the range of about 30 to 60 minutes.
  • the system can be readily removed by peeling it away from the surface of the teeth.
  • the tooth whitening composition can be worn for an extended period of time, but will typically be worn for a predetermined period of time of from about 10 minutes to about 24 hours.
  • a preferred time period is from about 10 minutes to about 1 hour, with about 30 minutes also being preferred.
  • a user can form the composition around the upper or lower teeth by applying normal manual pressure to the substrate with the tips of the fingers and thumbs, optionally by moistening the composition prior to application. Assuming the surface area of the average adult finger or thumb tip is approximately one square centimeter, the normal pressure generated by the finger and thumb tips is about 100,000 to about 150,000 Pascals (i.e., about 3 lbs. or 1.36 kg) per square centimeter. The pressure is typically applied to the composition by each finger and thumb tip for about one or two seconds. Once the pressure applied to the substrate by the tips of the fingers and thumbs is removed, the composition remains in the shape of, and adherent to, the surface of the teeth.
  • the composition can be removed simply by peeling it away from the surface of the teeth. If desired, the composition can be re-adhered for additional whitening time. Any residue left behind is minimal, and can be removed using conventional tooth cleansing methods.
  • the tooth whitening composition can also be applied as a non-solid composition, for example applied as a liquid or gel.
  • a non-solid composition for example applied as a liquid or gel.
  • the user can extrude the composition from a tube onto a finger for application to the teeth, extrude the composition from a tube directly onto the teeth, apply the composition by means of a brush or other applicator, and so forth. After the evaporation of solvent, the composition dries to form a matrix-type polymer film on the surface of the teeth.
  • the hydrogel contains sufficient water or other solvent to provide flowable property.
  • the polymer components of the liquid or gel composition are soluble in a water-ethanol mixture both at ambient temperature and at refrigeration temperatures of about 4°C, and are miscible upon solvent evaporation.
  • the polymeric composition has a Lower Critical Solution Temperature of about 36°C in an ethanol-water mixture.
  • the resulting film (after solvent evaporation) is preferably insoluble or slowly soluble in saliva at body temperature so as to provide lost lasting contact between the hydrogen peroxide and the dental enamel.
  • the hydrogen peroxide should be stable both in the liquid or gel composition, as well as within polymer film upon drying.
  • DSC Differential Scanning Calorimetry
  • Elasticity shear modulus of the adhesives in the linear viscoelastic regime G' , loss modulus G" and tan ⁇ were measured on a parallel plate Dynamical Mechanical Analyzer DMA 861 from Mettler Toledo, Switzerland.
  • the amplitude of shear deformation was chosen to be in the linear regime of the elastic modulus G' over the whole range of temperatures. In dependence on PSA properties and temperature, this zone corresponded to a deformation less than 3 ⁇ . All measurements were performed at the temperature 37 °C and at 1 Hz frequency.
  • DMA technique is a function of deformation frequency. At the frequency of 1 Hz, this value can be of 40 0 C higher than the true glass transitiontemperature, evaluated with DSC. For this reason, the former value can not be taken as a useful indicator of the PSA Stamm.
  • the jar with another sample was covered with a lid and stored in an incubator at 25 °C . Then the swollen sample was accurately taken from the jar and placed onto a release liner. Superficial excess moisture was accurately removed from the disk by careful blotting the sample with a Kimberly-Clark lab paper. Then the obtained swollen sample was weighed and the mass was recorded (m sw , g). The swollen sample was deposited into an oven at 60 °C and dried to constant weight. The mass of the dry sample was recorded (m dry , grams). The swell ratio (a, g/g) and sol fraction (SF, ) were calculated as follows:
  • compositions of hydrophilic bio-PSAs were prepared from the ingredients listed in Table 1.
  • compositions of the invention containing the components listed in Table 1 were prepared using a casting from solution followed by drying method. Weighed amounts of FFP, NCC and plasticizer were dissolved in ethanol, using a high- torque, low speed mixing arm stirrer. Homogeneous solutions were cast onto Loparex Release Liner PET-RL-001U and dried at room temperature overnight.
  • a uniform thickness of the films was obtained by using the BYK-Gardner film casting knife (AG- 4300 Series, Columbia, MD) as described earlier [Novikov M.B., Roos A., Creton C, Feldstein M.M., Dynamic mechanical and tensile properties of Poly(N-Vinyl Pyrrolidone)-Poly(ethylene Glycol) blends, Polymer, 2003, 44(12), 3559 - 3576]. Obtained films of 100 - 350 ⁇ in thickness were either transparent or translucent.
  • the bio-PSA compositions of the invention contained a polyacid Eudragit L-100-55 as a FFP, whereas the Examples 4 - 6 were based on polybases PVP K-90, Kollidon K-30 and Kollidon VA-64.
  • the composition on the Example 1 contained no polymeric NCC, while the compositions according Examples 2 - 6 where non-covalently crosslinked through the formation on interpolymer complexes.
  • the reference composition of the Example 4 corresponds to the U.S. Patent Applications Nos. 2003/0152528, 2003/0235549, and 2004/0105834 by P. Singh, G.W. Cleary, M.M. Feldstein, D.F.
  • Bairamov at al which are treated as the prototypes of present invention.
  • the reference film of Example 4 demonstrates good adhesion to teeth and appreciable adhesion toward mucosal tissues in oral cavity.
  • the composition is fastly dissolved, creating a sense of glue in a mouth. For this reason it needs in protecting backing film as is applied in tooth whitening formulations.
  • the FFP : NCC ratio is a measure of noncovalent bond network density that determines cohesive strength, dissolution and swelling of the bio-PSA film. As the FFP : NCC ⁇ 1, the noncovalent network becomes denser, solubility and swelling decrease and the cohesive strength rises.
  • the noncovalent network density governs the blend rigidity, dictating the magnitudes of the G' modulus.
  • the bio- PSA composition can be free of polymeric NCC.
  • carboxyl groups of film-forming polyacid should form hydrogen bonds with complementary low molecular weight component exemplified by carbamide (urea). Due to very short distance between the carbamide aminogroups, urea is hardly capable of noncovalent crosslinking the polyacid macromolecules.
  • the bio-PSA material also consists of noncovalent acid-base complex.
  • Tg glass transition temperature
  • Tg H2 o glass transition temperature of water.
  • the value of the glass transition temperature of the water is a subject of debates [N. Giovambattista, C.A. Angell, F. Sciortino, H.E. Stanley, Glass transition temperature of water: A simulation study, Phys. Rev. Let. 2004, v. 93 No. 4 pp. 047801-1 - 047801-4].
  • Tg H2 o 136 K.
  • the film When a dry, rigid nontacky hydrophilic polymer film is applied to teeth, the film swells and pressure sensitive character of adhesion appears as the result of Tg decrease due to a solid composition plasticization by absorbed water.
  • the film plasticization by the water is accompanied by its softening and the decrease of elasticity modulus G' until the range established by the Dahlquist's criterion of tack is achieved.
  • the G' values of PSAs at deformation frequency of 1 Hz are to be less than 0.3 MPa [Dahlquist C.A., Pressure-Sensitive Adhesives. in: Patrick R.L., Treatise on Adhesion and Adhesives, vol. 2, M. Dekker, N.Y., 219 - 260, 1969].
  • the values of storage (elasticity) modulus G' of swollen bio-PSA lie in the range from to 0.054 to 0.39 MPa, while the reference composition (Example 4) possessing non-targeted adhesion to teeth and others mucosal tissues in oral cavity demonstrates abnormally low G' value of 0.0065 MPa.
  • the G' value characterizes elastic material properties (the amount of mechanical energy stored by material in the course of deformation).
  • the G' behavior is in good correlation with that of loss modulus G" which varies between 0.047 and 0.32 MPa for the PSAs with targeted adhesion to teeth.
  • Tg is between -40 and -126 0 C
  • G' ⁇ 0.4 MPa tan ⁇ in the range from 0.69 to 1.11.
  • These values can be featured for hydrophilic polymers capable of swelling in water and possessing the swell ratio in the range from 2 to 15.
  • the content of sol fraction has a little or no effect on the selective adhesion behavior.
  • bioadhesive compositions with high sol fraction can be especially useful in night-time usable tooth-whitening products, which could self-erode after the active agent has been released or the desired therapeutic or cosmetic effect has been achieved, owing to gradual polymer film dissolution in saliva. All these factors should be provided in combination. If a value of a some single factor departs from this rule, selective adhesion vanishes.
  • the bio-PSA films Being immersed into liquid water or placed in mouth, the bio-PSA films demonstrate a phase separation. As a result, the swollen films become snow-white and closely adjoin to the teeth, accepting their relief. Due to strong adhesion to teeth and the lack of adhesion to tongue, gums, palate, lips and soft buccal tissues, the films provide freedom of speaking and demonstrate a sunny smile. Owing to this valuable quality, the bio-PSA films containing no tooth-care ingredients can be useful in cosmetology for temporary decoration of user teeth, in particular during interview, public performances, telecasts, etc.
  • a translucent composition can be also provided, and is worn without being obtrusive or noticeable to others.
  • the system can be designed without an active ingredient and finds utility as a protective dressing for tooth surface, e.g. canker sore, cold sore, etc or as a wound dressing.
  • Obtained films of 50 ⁇ in thickness were translucent and flexible.
  • the films manifested no adhesion to dry finger skin, but strong adhesion to teeth upon contact under slight pressure by finger.
  • the films exhibited wear time above 1 hr and no adhesion towards oral mucosa.
  • quantitative analysis for HP demonstrated zero content of active peroxide, implying that the hydrogen peroxide was decomposed in the course of sample preparation.
  • the carboxyl groups of a polyacid should be blocked by their hydrogen bonding with complementary functional groups of polymer NCC, oligomer or low molecular weight agent.
  • compositions of hydrophilic bio-PSA films for tooth whitening were prepared from the ingredients listed in Table 2.
  • tooth whitening bioadhesive films outlined by Examples 9 and 10 contain polyacid Eudragit L-100-55 as FFP.
  • the film corresponding to Example 9 includes CP.
  • the CP interaction with polyacid in solution leads to partial decomposition of HP.
  • the content of hydrogen peroxide in the film is about 2.4 wt %.
  • the polyacid was first mixed with urea and liquid HP was added to the mixture. This results in higher HP concentration in bioadhesive film (5.5 wt. %).
  • the uncrosslinked tooth whitening compositions described by Examples 9 and 10 refer to bioadhesive film described in Example 2. They possess excellent adhesion toward teeth and no mucoadhesion. Splendid adhesion defines long wearing the whitening films on teeth.
  • Tooth whitening films on Examples 11 - 16 contain polybase as FFP.
  • the film composition disclosed by Example 11 include high molecular weight PVP complex with HP (Peroxydone K-90) as FFP and the source of whitening agent.
  • HP Peroxydone K-90
  • the PVP is noncovalently crosslinked through comparatively short chains of PEG-400, bearing complementary hydroxyl groups on both ends of oligomer molecule. In this way, the PEG-400 simultaneously behaves as NCC and plasticizer of PVP. Because both components of the composition are water soluble, the bioadhesive film dissolves in saliva over 10 - 15 minutes.
  • Formulations 12 - 15 utilize the mixture of two polybases, PVP (Kollidon K-30) and vinyl pyrrolidone copolymer with 40 mol % of vinyl acetate (Kollidon VA64) as FFP.
  • PVP Kerdon K-30
  • Vollidon VA64 vinyl pyrrolidone copolymer with 40 mol % of vinyl acetate
  • the content of Kollidon VA 64 in blends with PVP increases from 31.8 (Example 12) to 40.2 wt % (Example 15). In contrast to PVP, the Kollidon VA64 is much less soluble in water.
  • the bio-PSA film on Example 16 contains pure Kollidon VA64 as the FFP and no PVP K-30.
  • the FFP:NCC ratio varies from 3.0 to 1.9. All the films demonstrate excellent adhesion to teeth and no mucoadhesion, defining the time of tooth whitening film wearing that exceeds 1 hour (at film thickness of 100 - 150 ⁇ ).
  • compositions 12 and 13 contain carbamide peroxide as tooth whitening agent, while all other films use 31 wt % aqueous solution of hydrogen peroxide.
  • composition 13 the carbamide peroxide is incorporated into film along with HP. All the formulations provide sufficient stability of the whitening agent in the process of film preparastion by casting - drying method. The procedure of film production is described above in Examples 1 - 6.
  • Examples 9 - 16 employ model polymers - Eudragit L-100-55 polyacid, and the vinyl pyrrolidone - based homo- and copolymers, polybases Kollidon K-30, K-90 and Kollidone VA64 - as FFP and NCC in tooth whitening compositions with selective adhesion to teeth. Nevertheless these hydrophilic polymers by no means exhaust a long list of components suitable for application in the bioadhesive platforms for tooth whitening strips. Some other eligible polymers are described in Examples 17 - 24.
  • PSA compositions with peroxides were prepared from the complementary functional polymers listed in Table 3.
  • compositions corresponding to the Examples 17 - 19 involve polybase Kollidon VA64 as FFP and carboxyl- or hydroxyl group containing cellulose derivatives as NCC.
  • the tooth whitening compositions outlined by the Examples 19 and 20 employ the mixtures of the carboxyl group containing polymeric NCC, Eudragit L-100-55, with the polymers bearing hydroxyl groups in thir recurring units, hydroxypropyl cellulose (HPC) and polyvinyl alcohol) (PVA).
  • HPC hydroxypropyl cellulose
  • PVA polyvinyl alcohol
  • the carboxyl groups form stronger hydrogen bonds than the hydroxyl groups. In this way, minor NCC (CPC or PVA) behave as compatibilizers between the NCC and FFP, facilitating the formation of more ductile interpolymer network.
  • Gantrez S 97 is a maleic acid copolymer with methylvinyl ether.
  • Example 22 indicates in comparison with Example 10, its hydrogen bonded complex with urea exhibits selective adhesion to the surface of teeth and provides the stability of absorbed hydrogen peroxide molecules.
  • the polyacids of different chemical structure can be used in bio-adhesive platforms for tooth whitening.
  • Examples 23 and 24 illustrate bioadhesive tooth whitening compositions based on vinyl pyrrolidone - vinyl caprolactam - acrylic tercopolymer polybases, Advantage HC- 37 and Aquaflex SF-40, both available from Ashland.
  • the third copolymer in the Advantage HC-37 is dimethylaminoethyl methacrylate, whereas the Aquaflex SF-40 contains dimethylaminopropyl methacrylamide. All the compositions provide perfect adhesion to teeth, no mucoadhesion, and hydrogen peroxide stability.
  • the glass transition temperature of swollen hydrogel measured in 10 min upon its immersion into aqueous medium - from -10 to -130 °C;
  • liquid and hydrogel compositions relating to solid tooth whitening formulations can be also applied to teeth surface in the form of relevant casting solutions in ethanol.
  • the method of liquid composition prepararion is illustrated by the following typical procedure.
  • a liquid composition for tooth whitening was prepared by mixing the following components with magnetic stirrer:
  • Liquid tooth whitening product is clear gel applied with a small brush or cotton bud directly to the surface of teeth. Put the gel straight onto exposed smiling teeth and dry for 30 s. Instructions generally call for twice a day application for 14 days. Initial results are seen in a few days and final results are sustained for about four months.
  • waxes I and II can be used, supplied by Wacker.
  • the strip coating with wax layer can be provided by casting-drying from hexane solution or from melt, using a paper applicator, by spraying one side of the strip with wax solution, and by applying the wax with small brush.
  • the first approach consists in the increase of moisture absorbing capacity of the composition and represents incoropration of water absorbents.
  • Suitable absorbents of moisture can be either in the form of particles, mixed with the composition, or in the form of hydrophilic woven and nonwoven materials, impregnated by the adhesive.
  • Particle absorbents include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesium silicate, starch, calcium sulfate, calcium stearate, calcium phosphate, clays such as laponite, polyacrylamide known under trademark Water Lock ® Superabsorbent Polymer, available from SNI Solutions. Appropriate woven and nonwoven fabrics can be separated from the class of paper and cotton materials.
  • Alternative approach to enhance creep resistance of tooth-whitening composition relates to the increase of noncovalent crosslinking density.
  • the FFP'.NCC concentration ratio should be decreased, tending to unity.
  • the increase in creep resistance can be achieved by mixing the adhesive composition with inert fillers, i,e. polyurethane polyether amide copolymers, polyesters and polyester copolymers, nylon and rayon.
  • a preferred filler is colloidal silica, e.g. Cab-O-Sil ® (Cabot Corporation, Boston Mass).

Abstract

La présente invention concerne des compositions d'hydrogel adhésives, à savoir des films bioadhésifs sensibles à la pression absorbant l'eau, « intelligents », qui possèdent une forte adhérence ciblée vis-à-vis des dents mais n'adhèrent pas à d'autres tissus muqueux dans la cavité buccale. Les compositions comprennent un polymère hydrophile, filmogène, et d'autres composants polymères oligomères ou de faible masse moléculaire, hydrophiles, assurant une formation de complexe avec des valeurs particulières de température de transition vitreuse, de module d'élasticité G, de tangente d'angle de perte, de degré de gonflement et de rapport de gonflement. Le polymère hydrophile, filmogène, est présent dans une concentration plus élevée que les autres composants de la composition, et ce dernier contient des groupes fonctionnels réactifs complémentaires qui sont aptes à former des liaisons hydrogène, électrostatiques ou ioniques non covalentes avec les groupes fonctionnels du polymère filmogène hydrophile. A l'état gonflé, le bioadhésif sensible à la pression, hydrophile, « intelligent », est plus souple que le substrat dentaire mais plus dur que les tissus muqueux dans la cavité buccale. Les compositions trouvent leur utilité comme bandes ou gels de blanchissement de dents et, dans ce but, contiennent un agent de blanchiment, de préférence un peroxyde.
PCT/RU2012/000377 2012-04-27 2012-05-14 Bioadhésifs sensibles à la pression, hydrophiles, ayant une adhérence ciblée vis-à-vis des dents et compositions pour soins dentaires à base de ceux-ci WO2013162404A1 (fr)

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RU2012116982 2012-04-27
RU2012116982/15A RU2517142C2 (ru) 2012-04-27 2012-04-27 Гидрофильный чувствительный к давлению биоадгезив с целенаправленной адгезией к зубам и композиция для ухода за зубами на его основе

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WO2016131642A1 (fr) * 2015-02-17 2016-08-25 Koninklijke Philips N.V. Système de blanchiment des dents monocouche
WO2017149326A1 (fr) * 2016-03-03 2017-09-08 Ascenticus Pharma Limited Compositions dentaires
CN107282124A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及四聚方法
CN107282130A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 乙烯四聚催化剂组合物及其应用
CN107282132A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及应用
CN107282122A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及其应用
CN107282121A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯齐聚用催化剂组合物和齐聚方法
CN107282123A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯齐聚催化剂组合物及其应用
WO2018005535A1 (fr) * 2016-06-27 2018-01-04 William Marsh Rice University Compositions adhésives à base de fluor et d'hydrogène et procédés pour les préparer
WO2018118506A1 (fr) * 2016-12-20 2018-06-28 Colgate-Palmolive Company Compositions de soins buccaux
US10064802B2 (en) 2013-09-11 2018-09-04 3M Innovative Properties Company Oral compositions, dental structures and methods of delivering oral compositions
WO2018215789A1 (fr) * 2017-05-26 2018-11-29 Biofilm Limited Composition de soin buccal, son procédé de préparation et son procédé d'utilisation
US10772821B2 (en) 2013-09-11 2020-09-15 3M Innovative Properties Company Oral compositions
CN115811968A (zh) * 2020-05-05 2023-03-17 必修复有限公司 可溶解的过氧化氢牙齿美白贴或牙齿美白膜
CN115813805A (zh) * 2022-11-25 2023-03-21 苏州中化药品工业有限公司 一种新型口腔牙齿清洁剂及其制备方法
US11723863B2 (en) 2018-06-22 2023-08-15 Church & Dwight Co., Inc. Oral care compositions comprising benzocaine and mucoadhesive thin films formed therefrom
WO2023171555A1 (fr) * 2022-03-10 2023-09-14 積水化学工業株式会社 Agent inhibiteur d'infection virale, particules inhibitrices d'infection virale, et matériau de revêtement inhibiteur d'infection virale

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RU181363U1 (ru) * 2017-11-16 2018-07-11 Виктор Николаевич Долинский Вкладка для полости рта
CN108362815B (zh) * 2018-01-08 2020-11-06 哈尔滨理工大学 一种新型的l-色氨酸电化学传感器

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US10064802B2 (en) 2013-09-11 2018-09-04 3M Innovative Properties Company Oral compositions, dental structures and methods of delivering oral compositions
US20170020800A1 (en) * 2014-04-14 2017-01-26 3M Innovative Properties Company Oral compositions
WO2015160762A1 (fr) * 2014-04-14 2015-10-22 3M Innovative Properties Company Compositions orales
WO2016131642A1 (fr) * 2015-02-17 2016-08-25 Koninklijke Philips N.V. Système de blanchiment des dents monocouche
US10307348B2 (en) 2015-02-17 2019-06-04 Koninklijke Philips N.V. Single layer tooth whitening system
GB2553014A (en) * 2016-03-03 2018-02-21 Ascenticus Pharma Ltd Dental compositions
WO2017149326A1 (fr) * 2016-03-03 2017-09-08 Ascenticus Pharma Limited Compositions dentaires
CN107282132A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及应用
CN107282124A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及四聚方法
CN107282123A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯齐聚催化剂组合物及其应用
CN107282121A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯齐聚用催化剂组合物和齐聚方法
CN107282122B (zh) * 2016-03-31 2019-12-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及其应用
CN107282122A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 一种乙烯四聚催化剂组合物及其应用
CN107282130A (zh) * 2016-03-31 2017-10-24 中国石油化工股份有限公司 乙烯四聚催化剂组合物及其应用
WO2018005535A1 (fr) * 2016-06-27 2018-01-04 William Marsh Rice University Compositions adhésives à base de fluor et d'hydrogène et procédés pour les préparer
US11174418B2 (en) 2016-06-27 2021-11-16 William Marsh Rice University Fluorine and hydrogen-based adhesive compositions and methods of making the same
WO2018118506A1 (fr) * 2016-12-20 2018-06-28 Colgate-Palmolive Company Compositions de soins buccaux
AU2017382575B2 (en) * 2016-12-20 2020-01-30 Colgate-Palmolive Company Oral care compositions
WO2018215789A1 (fr) * 2017-05-26 2018-11-29 Biofilm Limited Composition de soin buccal, son procédé de préparation et son procédé d'utilisation
US11723863B2 (en) 2018-06-22 2023-08-15 Church & Dwight Co., Inc. Oral care compositions comprising benzocaine and mucoadhesive thin films formed therefrom
CN115811968A (zh) * 2020-05-05 2023-03-17 必修复有限公司 可溶解的过氧化氢牙齿美白贴或牙齿美白膜
WO2023171555A1 (fr) * 2022-03-10 2023-09-14 積水化学工業株式会社 Agent inhibiteur d'infection virale, particules inhibitrices d'infection virale, et matériau de revêtement inhibiteur d'infection virale
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