MXPA05012618A - Hydrogel composition demonstrating phase separation - Google Patents
Hydrogel composition demonstrating phase separationInfo
- Publication number
- MXPA05012618A MXPA05012618A MXPA/A/2005/012618A MXPA05012618A MXPA05012618A MX PA05012618 A MXPA05012618 A MX PA05012618A MX PA05012618 A MXPA05012618 A MX PA05012618A MX PA05012618 A MXPA05012618 A MX PA05012618A
- Authority
- MX
- Mexico
- Prior art keywords
- water
- polymer
- further characterized
- composition according
- composition
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 358
- 238000005191 phase separation Methods 0.000 title claims description 13
- 239000000017 hydrogel Substances 0.000 title description 43
- 210000000515 Tooth Anatomy 0.000 claims abstract description 109
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 109
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 73
- 230000000295 complement Effects 0.000 claims abstract description 61
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 23
- 230000002087 whitening Effects 0.000 claims abstract description 23
- 229920003176 water-insoluble polymer Polymers 0.000 claims abstract description 22
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 127
- 229920000642 polymer Polymers 0.000 claims description 126
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 90
- -1 polyvinylamine Polymers 0.000 claims description 57
- 238000004061 bleaching Methods 0.000 claims description 48
- 239000007844 bleaching agent Substances 0.000 claims description 42
- 150000002978 peroxides Chemical class 0.000 claims description 39
- 229920001577 copolymer Polymers 0.000 claims description 33
- 229920002678 cellulose Polymers 0.000 claims description 25
- 229920001223 polyethylene glycol Polymers 0.000 claims description 24
- AQLJVWUFPCUVLO-UHFFFAOYSA-N Hydrogen peroxide - urea Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 claims description 18
- 229940078916 carbamide peroxide Drugs 0.000 claims description 15
- 239000000178 monomer Substances 0.000 claims description 15
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims description 14
- 239000002202 Polyethylene glycol Substances 0.000 claims description 12
- 239000000975 dye Substances 0.000 claims description 12
- 150000004965 peroxy acids Chemical class 0.000 claims description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 11
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- 230000015572 biosynthetic process Effects 0.000 claims description 9
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims description 8
- QBWCMBCROVPCKQ-UHFFFAOYSA-M chlorite Chemical class [O-]Cl=O QBWCMBCROVPCKQ-UHFFFAOYSA-M 0.000 claims description 8
- 238000005755 formation reaction Methods 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 8
- 239000002184 metal Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 239000000654 additive Substances 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
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- 235000003599 food sweetener Nutrition 0.000 claims description 7
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000003765 sweetening agent Substances 0.000 claims description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-N methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 239000002562 thickening agent Substances 0.000 claims description 6
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- OSVXSBDYLRYLIG-UHFFFAOYSA-N Chlorine dioxide Chemical compound O=Cl=O OSVXSBDYLRYLIG-UHFFFAOYSA-N 0.000 claims description 4
- WQYVRQLZKVEZGA-UHFFFAOYSA-N Hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 claims description 4
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- 239000003623 enhancer Substances 0.000 claims description 4
- 102000008186 Collagen Human genes 0.000 claims description 3
- 108010035532 Collagen Proteins 0.000 claims description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002845 Poly(methacrylic acid) Polymers 0.000 claims description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M Sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 claims description 3
- DQEFEBPAPFSJLV-WLTGXWPBSA-N [(2R,3R,4S,5R,6S)-4,5,6-tri(propanoyloxy)-3-[(2S,3R,4S,5R,6R)-3,4,5-tri(propanoyloxy)-6-(propanoyloxymethyl)oxan-2-yl]oxyoxan-2-yl]methyl propanoate Chemical group CCC(=O)OC[C@H]1O[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@@H](OC(=O)CC)[C@@H]1O[C@H]1[C@H](OC(=O)CC)[C@@H](OC(=O)CC)[C@H](OC(=O)CC)[C@@H](COC(=O)CC)O1 DQEFEBPAPFSJLV-WLTGXWPBSA-N 0.000 claims description 3
- VUNGHBJEVBKTME-UHFFFAOYSA-N [NH-]C=C Chemical class [NH-]C=C VUNGHBJEVBKTME-UHFFFAOYSA-N 0.000 claims description 3
- 230000000996 additive Effects 0.000 claims description 3
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- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 3
- 150000004676 glycans Polymers 0.000 claims description 3
- CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 3
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- LHJQIRIGXXHNLA-UHFFFAOYSA-N Calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004155 Chlorine dioxide Substances 0.000 claims description 2
- WOHVONCNVLIHKY-UHFFFAOYSA-L [Ba+2].[O-]Cl=O.[O-]Cl=O Chemical compound [Ba+2].[O-]Cl=O.[O-]Cl=O WOHVONCNVLIHKY-UHFFFAOYSA-L 0.000 claims description 2
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- NWAPVVCSZCCZCU-UHFFFAOYSA-L magnesium;dichlorite Chemical compound [Mg+2].[O-]Cl=O.[O-]Cl=O NWAPVVCSZCCZCU-UHFFFAOYSA-L 0.000 claims description 2
- 150000002976 peresters Chemical class 0.000 claims description 2
- VISKNDGJUCDNMS-UHFFFAOYSA-M potassium;chlorite Chemical compound [K+].[O-]Cl=O VISKNDGJUCDNMS-UHFFFAOYSA-M 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 3
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- XFIPBHVSZAZCKV-UHFFFAOYSA-M sodium;5-chloro-2-(2,4-dichlorophenoxy)phenol;fluoride Chemical compound [F-].[Na+].OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XFIPBHVSZAZCKV-UHFFFAOYSA-M 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- 238000000034 method Methods 0.000 description 24
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 21
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- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N tributyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 1
- WKMXOPXIVBEXRR-UHFFFAOYSA-H tricalcium;diphosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O WKMXOPXIVBEXRR-UHFFFAOYSA-H 0.000 description 1
- AMMPRZCMKXDUNE-UHFFFAOYSA-N trihexyl 2-hydroxypropane-1,2,3-tricarboxylate Chemical compound CCCCCCOC(=O)CC(O)(C(=O)OCCCCCC)CC(=O)OCCCCCC AMMPRZCMKXDUNE-UHFFFAOYSA-N 0.000 description 1
- AISMNBXOJRHCIA-UHFFFAOYSA-N trimethylazanium;bromide Chemical compound Br.CN(C)C AISMNBXOJRHCIA-UHFFFAOYSA-N 0.000 description 1
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- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- GGSOCIMBTRWRJF-UHFFFAOYSA-L zinc;undec-2-enoate Chemical compound [Zn+2].CCCCCCCCC=CC([O-])=O.CCCCCCCCC=CC([O-])=O GGSOCIMBTRWRJF-UHFFFAOYSA-L 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Abstract
A composition is provided, wherein the composition comprises a water-swellable, water-insoluble polymer or a water-soluble polymer, a blend of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer. The composition also includes a second water-swellable, water-insoluble polymer that provides for a phase separating film forming composition. Active ingredients, such as a whitening agent, may be included. The composition finds utility as an oral dressing, for example, a tooth whitening composition that is applied to the teeth in need of whitening, and removed when the degree of whitening has been achieved. In certain embodiments, the composition is translucent. Methods for preparing and using the compositions are also disclosed.
Description
HIDROGEL COMPOSITIONS THAT DEMONSTRATE PHASE SEPARATION AFTER CONTACT WITH AQUEOUS MEDIA
TECHNICAL FIELD
This invention relates generally to hydrogel compositions. More particularly, the invention relates to hydrogel compositions useful as dressings or protectants, and for administering a wide variety of active agents to the skin and tissue of mucous membranes such as the mouth, including dental whiteners.
TECHNICAL BACKGROUND
Discoloration of teeth occurs widely in society, and is estimated to occur in two out of three adults. Dental discoloration is considered an imperfection or aesthetic defect, and can have negative consequences in the life of the affected person, causing inhibition, even inhibition of the smile. Dental discoloration can be particularly distressing or problematic in situations and professions where showing clean white teeth is essential. A tooth comprises an inner dentin layer and a hard outer enamel layer that is slightly porous. The outer layer is the protective layer of the tooth. The natural color of the tooth is opaque to translucent white or slightly whitish. The staining of the teeth arises as a result of exposure of compounds such as tannins and other polyphenolic compounds to the teeth. These compounds become trapped or remain attached to the proteinaceous layer on the surface of the teeth, and can penetrate enamel and even dentin. Occasionally, staining may arise from sources inside the tooth, such as tetracycline, which may become deposited on the teeth if administered to an individual when young. The staining of the surface can usually be removed by mechanical dental cleaning. However, dentin or bleached enamel is not subject to mechanical methods of dental cleaning, and mechanical methods are required that can penetrate the structure of the tooth, to remove stains. The most effective treatments for tooth discoloration are compositions containing an oxidizing agent, such as hydrogen peroxide, which is capable of reacting with the chromogenic molecules responsible for the discoloration, rendering them colorless or water soluble, or both. Accordingly, dental bleaching compositions generally fall into two categories: (1) gels, pastes or liquids, which include toothpastes that are mechanically agitated on the stained surface of the tooth, to affect the removal of the tooth stain through the tooth. abrasive erosion of surface spots; and (2) gels, pastes or liquids that achieve a dental bleaching effect by a chemical procedure, while in contact with the stained surface of the tooth for a specified period, after which the formulation is removed. In some cases, an auxiliary chemical process, which can be oxidative or enzymatic, complements the mechanical procedure. Some dental compositions such as dentifrices, toothpastes, gels and powders contain bleaching agents that release hydrogen peroxide or active oxygen. Such bleaching agents include peroxides, percarbonates and perborates of the alkali metal and alkaline earth metals or complex compounds containing hydrogen peroxide. Also, peroxide salts of the alkali or alkaline earth metals are known to be useful in the bleaching of teeth. Of the many peroxides available to the formulator of dental bleaching compositions, hydrogen peroxide (and its adducts or association complexes, such as carbamide peroxide and sodium percarbonate) have been used almost exclusively. The chemistry of hydrogen peroxide is well known, although the specific nature of its interactions with the chromogens of the tooth is poorly understood. It is thought that hydrogen peroxide destroys the chromogens of the tooth by oxidizing carbon-carbon, carbon-oxygen and carbon-nitrogen unsaturated bonds present in the molecules of the stain, making them in this way colorless or soluble. A related class of compounds, peroxyacids, have been used in laundry detergents to effectively launder clothes, mainly due to their stability in solution and their binding capabilities specific to certain types of stain molecules. Many stable solid peroxyacids have been used, including diperoxydodecanoic acid and the magnesium salt of monoperoxyphthalic acid. Other peroxyacids, such as peroxyacetic acid, are available as solutions containing an equilibrium distribution of acetic acid, hydrogen peroxide, peroxyacetic acid and water. Alternatively, a peroxide donor such as sodium perborate or sodium percarbonate, is formulated together with a peroxyacid precursor. Upon contact with water, the peroxide donor releases hydrogen peroxide, which then reacts with the peroxyacid precursor to form the real peroxyacid. Examples of peroxyacids created in situ include peroxyacetic acid (from hydrogen peroxide and tetraacetylethylenediamine) and peroxynanoaneic acid (from hydrogen peroxide and nonanoyloxybenzene sulfonate). Peroxyacids have also been used in oral care compositions for bleaching stained teeth. The patent of E.U.A. No. 5,279,816 to Church et al., Discloses a method of tooth whitening comprising the application of a composition containing peroxyacetic acid having an acidic pH. EP 545,594 to Church ef al., Describes the use of peroxyacetic acid in the preparation of a composition for dental bleaching. The peroxyacetic acid may be present in the composition, or alternatively, it may be generated in situ by combining a peroxide source with a peroxyacetic acid precursor during use.
For example, the patent of E.U.A. No. 5,302,375 to Viscio discloses a composition that generates peroxyacetic acid within a vehicle in situ by combining water, acetylsalicylic acid and a water-soluble alkali metal percarbonate. The most commonly used dental bleaching agent is carbamide peroxide (CO (NH2) 2H2? 2), also called hydrogen peroxide and urea, hydrogen peroxide carbamide and perhydrol-urea. Carbamide peroxide had been used by dental clinicians for several decades as an oral antiseptic, and tooth whitening was an observed side effect of extended contact time. Counter compositions of 10% carbamide peroxide, are available as GLY-OXIDE® by Marion Laboratories, and PROXIGEL® by Reed and Camrick, which are low viscosity compositions that must be kept in a similar tray or container to provide contact with teeth. A bleaching gel that is capable of maintaining a comfortable adjustment dental tray in position for an extended period is available under the trademark OPALESCENCE® from Ultradent Products, Inc. in South Jordan, Utah. In order for said compositions to remain 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 adjustment, so that the tray does not exert pressure or cause irritation to the teeth or gums of the person. Said bleaching compositions must necessarily be formulated to be sufficiently tacky and viscous to resist dilution by saliva. In a method of bleaching an individual's teeth, a dental professional will construct a custom-made dental bleach tray for the patient from an impression made of the patient's dentition, and prescribe the use of an oxidizing gel that is It will be dispensed in the bleach tray and used intermittently for a period of approximately two weeks to approximately six months, depending on the severity of the staining of the teeth. Oxidizing compositions, usually packaged in small syringes or plastic tubes, are dispensed directly by the patient into the custom-made dental bleach tray, and held in place in the mouth for contact times of greater than about 60 minutes, times as much as 8 to 12 hours. The low bleaching rate is largely a consequence of the nature of the formulations that are developed to maintain the stability of the oxidizing composition. For example, the patent of E.U.A. No. 6,368,576 to Jensen, discloses dental bleaching compositions that are preferably used with a tray, so that the composition is maintained adjacent to the tooth surfaces of the person to be treated. These compositions are described as a sticky matrix material which is formed by combining a sufficient amount of a tackifier, such as carboxypolymethylene, with a solvent, such as glycerin, polyethylene glycol or water.
In another example, the patent of E.U.A. No. 5,718,886 to Pellico discloses a dental bleaching 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. Another example is described in the patent of E.U.A. No. 6,419,905 to Hernández, which describes the use of compositions containing carbamide peroxide (0.3-60%), xylitol (0.5-50%), a potassium salt (0.001-10%) and a fluorine salt (0.15-). 3%), formulated in a gel containing between 0.5 and 6% by weight of a suitable gelling agent. A tooth whitening composition that adheres to teeth is described in the U.S. Patents. Nos. 5,989,569 and 6,045,811 to Dirksing. According to these patents, the gel contains 30-85% glycerin or polyethylene glycol, 10-22% urea complex / hydrogen peroxide, 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 1 / second), and is sufficiently adhesive to avoid the need for a tray. Currently available teeth whitening compositions have a significant disadvantage because they cause dental sensitization in more than 50% of patients. The tooth sensitivity can result from the movement of fluid through the tubules of the dentin, which is detected 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 after exposure of the teeth to heat, cold, excessively sweet substances and other causative agents. Prolonged exposure of teeth to bleaching compositions, as practiced today, has many adverse effects in addition to that of tooth sensitivity. These adverse effects include calcium leaching from the enamel layer at a pH of less than 5.5; penetration of the intact enamel and dentin by the bleaching agents and risk of damage to the pulp tissue; and diluting the bleaching compositions with the saliva, which results in leaching of the dental tray and subsequent ingestion by the user. Some oxidizing compositions (which generally have relatively high concentrations of oxidants) are applied directly to the tooth surface of a patient in a dental office under the supervision of a dentist or dental hygienist. Theoretically, these dental bleaching strategies give faster results and better patient satisfaction in general. However, due to the high concentration of oxidizing agents contained in these so-called "office" compositions, they can be dangerous for the patient and the medical professional if they are not handled with care. The soft tissues of the patient (the gum, lips and other mucosal surfaces) must be isolated first of the potential exposure to the active oxidizing agent by using a perforated rubber sheet (known as a rubber dam), so that only the teeth protrude . Alternatively, the soft tissue can be isolated from the oxidants to be used in the bleaching process, covering the soft tissue with a polymerizable composition that is shaped to conform to the contours of the gingiva and subsequently cured by exposure to a source of high intensity light. Once the soft tissue has been isolated and protected, the medical professional can apply the oxidizing agent directly on the stained surfaces of the tooth for a specified period, or until a sufficient change in tooth color has occurred. The typical results obtained by using a dental whitener from the office vary from approximately 2 to 3 shades (measured with the VITA shade guide, VITA Zahnfarbik). The range of dental nuances in the shade guide VITA varies from very light (B1) to very dark (C4). A total of 16 dental nuances make up the full range of colors between these two terminal points on a scale of brilliance. Patient satisfaction with a dental whitening procedure increases with the number of changes in dental nuances achieved, with a generally accepted minimum desirable change of approximately 4 to 5 VITA shades. It is desirable, with respect to dental care products for tooth whitening, to provide dental care products that use an adhesive hydrogel that includes a bleaching agent to remove spots from an individual's teeth. In addition, there is a constant need for the development of products that provide a protective or protective dressing for the skin and mucosal surfaces, or that provide for the supply of active agents, for example, transdermal and transmucosal delivery of active agents to the skin, mucous tissues. , surface of the teeth, gums, mucous membranes and other oral tissue. Compositions are desired which do not require the use of dental trays to provide contact between the active agent and the teeth or other oral surface. Such products would ideally cause minimal sensitivity or no dental sensitivity, minimize or eliminate leakage of active agent resulting in ingestion by the user or resulting in damage or irritation to the gums or mucous membranes of the mouth, would provide longer duration of use , sustained dissolution of the active agent, improved efficacy, and would be well tolerated by patients. It would also be desirable to provide a dental care product that is a solid, self-adhesive composition but that does not adhere to the wearer's fingers, or that is not a solid (e.g., liquid or gel), and that forms a film when dry . The present invention addresses these needs.
BRIEF DESCRIPTION OF THE INVENTION
One aspect of the invention relates to a composition comprising: a water insoluble polymer swellable in water or a water soluble polymer; and a mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer. An active agent such as a tooth whitening agent may also be included. In one embodiment, the composition further comprises a water insoluble second water swellable polymer having different solubility and pH characteristics, than the first water insoluble polymer swellable in water or water soluble polymer. Another aspect of the invention pertains to a phase separating film forming composition comprising: a first water swellable polymer that is water soluble at a pH of less than about 5.5 or a water soluble polymer; a mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer; a second water-swellable polymer that is insoluble in water at all pH values; and an optional active agent. The composition undergoes phase separation once in use, forming a plurality of film layers. In a preferred embodiment, the first water insoluble water-swellable polymer is an acrylate-based polymer or copolymer; the hydrophilic polymer is a poly (N-vinyl lactam), poly (N-vinyl amide), poly (N-alkyl acrylamide), or copolymer and mixture thereof; the complementary oligomer capable of hydrogen bonding to the hydrophilic polymer is a polyalkylene glycol or a carboxyl-terminated polyalkylene glycol, and the second water-swellable water-insoluble polymer is a cellulose ester, or an acrylate-based polymer or copolymer. A preferred active agent is a bleaching agent such as a peroxide. The composition optionally comprises a low molecular weight plasticizer, and may also comprise at least one additive selected from the group consisting of flavorings, sweeteners, fillers, preservatives, pH regulators, softeners, thickeners, colorants (eg, pigments, dyes) , refringent particles, etc.), flavors (e.g., sweeteners, flavors), stabilizers, surface active agents, firmness agents and tackifiers. In a preferred method of using the composition, the composition is a tooth whitening composition, and it is applied to the teeth that need bleaching, and is then removed when the degree of bleaching has been achieved. In certain embodiments, the tooth whitening composition is translucent, and the composition is removed when the user is satisfied with the degree of bleaching achieved. Another aspect of the invention pertains to a composition comprising a first polymer insoluble in water swellable in water or a water soluble polymer; a second polymer insoluble in water swellable in water; a mixture 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, metal chlorites, perborates, percarbonates, peroxyacids, and combinations thereof.
Another aspect of the invention relates to a method for preparing a hydrogel film suitable for incorporation into a transmucosal or transdermal composition or system for oral care. This method comprises preparing a solution or a gel of a first polymer insoluble in water swellable in water or a water soluble polymer; a second polymer insoluble in water swellable in water; a hydrophilic polymer; and a complementary oligomer capable of hydrogen bonding or by 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 period in the range of about 1 to about 4 hours, thereby providing a hydrogel film on the substrate. In another method for forming a composition of the invention, the method comprises melt-processing through an extruder a mixture of a water-swellable water-insoluble first polymer or a water-soluble polymer.; a second polymer insoluble in water swellable in water; a hydrophilic polymer; and a complementary oligomer capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, to form an extruded composition; wherein the composition is extruded as a film of desired thickness onto a suitable substrate. The method further comprises charging the hydrogel film with an active agent such as a bleaching agent, thereby providing a dental bleaching composition. The adhesive compositions of the invention provide many significant advantages over the prior art. In particular, the present compositions: (1) provide ease of handling; (2) are easily modified during manufacture, so that properties such as adhesion, absorption, translucency and swelling can be controlled and optimized; (3) can be formulated so that the tack increases or decreases in the presence of moisture, so that the composition is not tacky until it becomes wet; (4) minimize the leakage of the active agent, when included, from the composition on a surface of the skin or a mucosal surface (e.g., in the mouth of the user); (5) can be manufactured in translucent form, allowing the user to see the degree of bleaching without removing the hydrogel composition from the teeth or the surface of the skin / mucosa; (6) minimize damage to the gums or mucous membranes in the mouth; (7) can be used comfortably and discreetly; (8) are easily removed from the teeth or the surface of the skin / mucosa, and leave no residue;
(9) are subject to extended duration of use or action; and (10) can provide sustained and controlled release of a variety of active agents.
DETAILED DESCRIPTION OF THE INVENTION
I. Definitions and nomenclature Before the present invention is described in detail, it will be understood that unless stated otherwise, this invention is not limited to hydrogel materials or specific manufacturing processes, since they may vary. It will also be understood that the terminology used herein is for the sole purpose of describing particular embodiments, and is not intended to be limiting. It should be noted that, as used in this specification and in the appended claims, the singular forms "a", "an" and "the" include plural references, unless the context clearly dictates otherwise. Thus, for example, the reference to "a hydrophilic polymer" includes not only an individual hydrophilic polymer, but also a combination or mixture of two or more different hydrophilic polymers, the reference to "a plasticizer" includes a combination or mixture of two or more different plasticizers, as well as an individual plasticizer, and the like. In the description and claim of the present invention, the following terminology will be used according to the definitions set forth below. The definitions of "hydrophobic" and "hydrophilic" polymers are based on the amount of water vapor absorbed by polymers at 100% relative humidity. According to this classification, the hydrophobic polymers absorb only up to 1% by weight of water at 100% relative humidity, while the moderately hydrophilic polymers absorb from 1 to 10% by weight of water, the hydrophilic polymers are able to absorb more of 10% by weight of water, and the hygroscopic polymers absorb more than 20% by weight of water. A "water-swellable" polymer is one that absorbs an amount of water greater than at least 25% by weight of its own weight, and preferably at least 50% by weight of its own weight, after immersion in a medium aqueous. The term "interlaced" refers herein to a composition that contains intramolecular and / or intermolecular entanglements, whether arising through covalent or non-covalent binding. "Non-covalent" bond, includes bonding by hydrogen bonds and electrostatic (ionic) bonding. The term "polymer" includes linear and branched polymer structures, and also encompasses entangled polymers, as well as copolymers (which may or may not be interlaced), thus including block copolymers, alternating copolymers, random copolymers, and the like. The compounds referred to herein as "oligomers", are polymers having a molecular weight less than about 1000 Da, preferably less than about 800 Da. The term "hydrogel" is used in the conventional sense to refer to water-swellable polymer matrices that can absorb a substantial amount of water to form elastic gels, where "matrices" are three-dimensional networks of macromolecules bonded together by covalent interlaces or not covalent After placement in an aqueous environment, the dried hydrogels swell to the level allowed by the degree of entanglement. The term "phase" is traditionally defined as a homogeneous part of a heterogeneous system. Respectively, "phase separation" is the transformation of a homogeneous system to a heterogeneous one. Conventionally, the phase separation process is achieved with the formation of an interface boundary between the phases of different composition. Typical examples of phase separation include sol-gel transition, precipitation in solution, or spontaneous formation of a multilayer (laminated) structure. The terms "active agent", "pharmacologically active agent" and "drug" are used herein to refer to a chemical compound or material that induces a desired pharmacological physiological effect., and include agents that are therapeutically effective, prophylactically effective or cosmetically effective. The terms also encompass pharmaceutically acceptable and pharmacologically active derivatives, and analogues of the active agents specifically mentioned herein including, but not limited to, salts, esters, amides, prodrugs, active metabolites, inclusion complexes, analogs, and the like. When the terms "active agent", "pharmacologically active agent" and "drug" are used, it will be understood that the active agent per se is included, as well as salts, esters, amides, prodrugs, active metabolites, inclusion complexes, analogues, etc., pharmaceutically acceptable and pharmacologically active. The term "tooth whitening composition" refers to a composition containing a hydrogel, as defined herein, and a bleaching agent. The term "bleaching agent" typically refers to an oxidizing agent such as a peroxide or a chlorite, as will be discussed in greater detail below. In some cases, the bleaching agent can be an enzyme or other catalytic means to remove a stain from the teeth. The bleaching agent may include one or more bleaching agents, surfactants, anti-plaque agents, dental anti-tanning agents and additional abrasive agents. The bleaching agent may have additional therapeutic benefits. The term "effective amount" or "a cosmetically effective amount" of a cosmetically active agent means a non-toxic but sufficient amount of a cosmetically active agent that provides the desired cosmetic effect. The term "effective amount" or "a therapeutically effective amount" of a pharmacologically active drug or agent is used to indicate a non-toxic but sufficient amount of the drug or agent that provides the desired therapeutic effect. The amount that is "effective" will vary from subject to subject, depending on the age and general condition of the individual, the agent or the particular active agents, and the like. In this way, it is not always possible to specify an exact "effective amount". However, an "effective" amount suitable in some individual case may be determined by the person skilled in the art using routine experimentation. In addition, the exact "effective" amount of an active agent incorporated into a composition or dosage form of the invention is not critical, so long as the concentration is within a sufficient scale that allows for easy application of the formulation to supply an amount of active agent that is within a therapeutically effective scale. The term "surface" as in "surface of the oral cavity" or "body surface", is used to include body surfaces such as skin, nails and mucosal tissue (e.g., sublingual, buccal, vaginal, rectal, urethral ), as well as surfaces in and around the oral cavity (eg, teeth, lips, gums, mucous membranes), as well as the surface of various skin wounds. "Transdermal" and "transmucosal" drug delivery means the administration of a drug to the skin or tissue surface of mucous membranes of an individual, such that the drug passes through the skin or tissue of mucous membranes and into the bloodstream of the patient. individual, thus providing a systemic effect. The term "transmucosal" is used to include the administration of a drug to the mucosal surface (eg, sublingual, buccal, vaginal, rectal, urethral) of an individual, so that the drug passes through the mucosal tissue and in the individual's bloodstream. The terms "transdermal" and "transmucosal" are used to encompass local and systemic effects, and therefore include topical administration, i.e., delivery of a topical agent to the skin or mucosa as in, for example, the treatment of various disorders. of the skin or mucous membranes to provide a local effect. The terms "stickiness" and "stickiness" are qualitative. Nevertheless, the terms "substantially non-sticky", "slightly sticky" and "sticky", as used herein, can be quantified using the values obtained in a method of determining stickiness PKI or TRBT, in the following manner. By "substantially non-tacky" is meant a hydrogel composition having a tack value that is less than about 25 g-cm / sec, by "slightly sticky" is meant a hydrogel composition having a tack value in the scale of about 25 g-cm / sec to about 100 g-cm / sec, and by "stickiness" is meant a hydrogel composition having a tack value of at least 100 g-cm / sec. The term "water insoluble" refers to a compound or composition whose solubility in water is less than 5% by weight, preferably less than 3% by weight, more preferably less than 1% by weight (measured in water at 20 °. C). Similarly, the term "water soluble" refers to a compound or composition whose solubility in water is greater than 5% by weight, preferably greater than 3% by weight, more preferably greater than 1% by weight (measured in water at 20 ° C). The term "translucent" is used herein to indicate a material capable of transmitting light, so that objects or images can be seen through the material. The translucent materials herein may or may not be "transparent", meaning that the material is optically clear. The term "translucent" indicates that a material is not "opaque", in which case objects and images can not be seen through the material.
II. Compositions The composition of the invention comprises a water insoluble polymer swellable in water or a water soluble polymer, a mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and an optional active agent such as a bleaching agent. The composition also includes a second polymer insoluble in water swellable in water. In certain embodiments, one of the water-insoluble water-insoluble polymers, or both, are also capable of hydrogen bonding with the hydrophilic polymer. Similarly, in certain embodiments, one of the water-soluble polymer and the water-swellable water-insoluble polymer, or both, are also capable of hydrogen bonding with the hydrophilic polymer.
In one embodiment of a non-solid composition of the invention, the first water-insoluble water-swellable polymer (or the water-soluble polymer) and the second water-swellable water-insoluble polymer, represent approximately 0.1-20% by weight, of preferably about 4-15% by weight of the composition; and the hydrophilic polymer represents about 1-30% by weight, preferably about 5-25% by weight of the composition. In another embodiment of a non-solid composition of the invention, the first polymer insoluble in water swellable in water (or the water-soluble polymer), and the second polymer insoluble in water swellable in water, represent approximately 1-30% by weight , preferably about 5-25% by weight of the composition; and the hydrophilic polymer represents approximately 0.1-20% by weight, preferably approximately 4-15% by weight of the composition. The active agent, when present, may represent about 0.1-60% or by weight, preferably about 1-40% by weight of the non-solid composition. The complementary oligomer may represent approximately 0.1-20% by weight, preferably approximately 0.5-10% by weight of the non-solid composition. Optimally, the complementary oligomer represents about 1-85% by weight, preferably about 5-50% by weight of the hydrophilic polymer / complementary oligomer mixture, in a non-solid composition. In one embodiment of a solid composition of the invention, the first water swellable polymer (or water soluble polymer), and the second water insoluble water swellable polymer, represent about 1-20% by weight, preferably about 6- 12% by weight of the composition; and the hydrophilic polymer represents about 20-80% by weight, preferably about 40-60% by weight of the composition. In another embodiment of a solid composition of the invention, the first water swellable polymer (or water soluble polymer), and the second water insoluble water swellable polymer, represent about 20-80% by weight, preferably about 40- 60%) by weight of the composition; and the hydrophilic polymer represents about 1-20% by weight, preferably about 6-12% by weight of the composition. The active agent, when present, may represent about 0.1-60% by weight, preferably about 1-30% by weight of the solid composition. The complementary oligomer may represent about 10-50% by weight, preferably about 15-35% by weight of the solid composition. Optimally, the complementary oligomer represents about 10-80% by weight, preferably about 20-50% by weight of the hydrophilic polymer / complementary oligomer mixture, in a solid composition. In one embodiment, the composition is a tooth whitening composition, wherein the bleaching agent functions to whiten the tooth surface to which the composition is applied. However, the bleaching agent may have other utilities, for example, as a therapeutic agent or another type of cosmetic agent, for example, to lighten the skin.
Therefore, the compositions described herein may find utility as pharmaceutical compositions that will be applied to a body surface (eg, teeth, nails, skin, mucosa, etc.), for the treatment of a disease state. For example, hydrogen peroxide also has antiseptic and anti-acne properties, and is a bleaching agent. Therefore, the invention also contemplates the treatment of an infection or acne by applying a composition of the invention containing hydrogen peroxide, to a surface of the body. Other disease states include, by way of illustration and not limitation, fungal infections, acne, wounds, skin lightening, etc. In addition, many active agents can be incorporated into the composition of the invention to treat a variety of diseases affecting the oral cavity.
A. Water-swellable water-insoluble polymers and water-soluble polymers The first water-swellable water insoluble polymer forms part of the composition that comes in contact with the surface of the body and serves, for example, to provide adhesive properties or regulate properties of swelling and dissolution. The second insoluble water-swellable water polymer serves to provide a protective film layer on the layer that comes into contact with the body surface. The first and second water-insoluble water-insoluble polymers can be of the same general class of polymers, but each will be selected for having different solubility characteristics in aqueous media. The first polymer is selected to be insoluble in aqueous media, for example, water, within a selected pH range, typically pH less than about 5.5, that is, the first polymer has pH-dependent solubility. The first polymer will generally dissolve in aqueous media at a pH greater than 5.5. The second polymer is selected to be insoluble in aqueous media at all pH values, ie, the second polymer has insolubility independent of pH. In this way, when the composition is added to an aqueous environment such as the pH of 6 to 8 typically present in the oral cavity, phase separation occurs between the first polymer (which is soluble at high pH) and the second polymer. This results in the water-swellable water-insoluble second polymer which forms a film on the first polymer / hydrophilic polymer / complementary oligomer film. The outer film formed by the second polymer is insoluble in aqueous media, but it remains permeable in water. Over time, the underlying film layer dissolves and the outer film can be removed if left for a sufficient period to separate into tiny particles that are gradually entrained, for example, by saliva. The removal of the underlying film and the outer film can also be facilitated by gentle rubbing with the user's finger or with a toothbrush. The weight ratio of the first to the second insoluble water-swellable water polymer can be within the range of about 1: 3 to 3: 1. In a preferred embodiment, the ratio is within the range of about 1.5: 1 to 2: 1. The first and second water-insoluble water-insoluble polymers are polymers that are capable of swelling when immersed in an aqueous liquid. The polymers swell in general by at least 25% by weight and, preferably, by at least 50% by weight of their own weight when immersed in water or aqueous solution. In some embodiments using certain hydrophilic polymers, the composition can swell as much as 1400% by weight of its dry weight.
1. Water insoluble first water-swellable polymer The adhesion profile can also be adapted based on the type of polymer selected as the first polymer, the ratio of the composition and the level of water in the mixture. The first water-insoluble polymer swellable in water is selected to provide the desired adhesion profile with respect to hydration. That is to say, a composition is provided which is generally substantially non-tacky before contact with water, but which becomes sticky upon contact with a wet surface. The first water insoluble water swellable polymer is capable of at least some degree of swelling when immersed in an aqueous liquid, but is insoluble in water at pH values less than about 5.5, while being soluble at higher pH values , such as those found in the mouth. The first water-swellable water-insoluble polymer can be an acrylate-based polymer or copolymer, ie, a copolymer or polymer of acrylic acid ester or acrylic acid (an "acrylate" polymer). Acrylate polymers are particularly suitable for use as the first water swellable polymer, and are generally formed of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, ethyl methacrylate and / or other monomers of vinyl. Suitable acrylate polymers are the copolymers available under the trademark "Eudragit" from Rohm Pharma (Germany). The Eudragit® E, L, S, RL, RS and NE series copolymers are available 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 polymers of the series Eudragit L and Eudragit S. Such particularly preferred 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 copolymers Eudragit L 30D-55 and Eudragit L 100-55 is about 135,000 Da, with a ratio of free carboxyl groups to ester groups of about 1: 1. The Eudragit L 100-55 copolymer is generally insoluble in aqueous fluids having a pH less than 5.5, and is therefore particularly well suited for use as the first water-swellable polymer. Another particularly suitable methacrylic methacrylate-methacrylic acid copolymer is Eudragit S-100, which differs from Eudragit L 30D-55 in that the ratio of free carboxyl groups to ester groups is about 1: 2. Eudragit S-100 is insoluble at pH less than 5.5, but unlike Eudragit L 30D-55, it is poorly soluble in aqueous fluids having a pH on the scale of 5.5 to 7.0. This copolymer is soluble at pH 7.0 and higher. Eudragit L 100 can 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 lower than 6.0. Those skilled in the art will appreciate that Eudragit L 30D-55, L 100-55, L100 and S 100 can be replaced with other acceptable polymers having similar characteristics of pH-dependent solubility. Other suitable acrylate polymers are the methacrylic acid / ethyl acrylate copolymers available under the trademark "Kollicoat" from BASF AG (Germany). For example, Kollicoat MAE has the same molecular structure as Eudragit L 100-55. When the first water-swellable polymer is an acrylate or acrylic acid polymer, a hydrogel is provided which can be reversibly dehydrated, ie, after the removal of water and any other solvent, the dehydrated hydrogel can be reconstituted to its original state by adding water. In addition, hydrophilic hydrogels prepared with an acrylate / acrylic acid water swellable polymer are generally substantially non-tacky prior to contact with water, but become sticky upon contact with a wet surface, such as that found in water. the inside of the mouth, such as on the surface of the teeth. This property of being non-sticky prior to contact with water, allows positioning or repositioning on a selected surface before, or as the hydrogel becomes sticky. Once hydrated, the hydrogel becomes sticky and adheres to the surface of the teeth or surface of the skin / mucosa. Furthermore, acrylate-containing compositions can generally provide swelling in the range of about 400% to 1500% after immersion of the hydrogel composition in water or other aqueous liquid, at a pH of less than 5.5, although the ratio of the acrylate polymer the mixture of complementary oligomer / hydrophilic polymer can be selected, so that the speed and the degree of swelling in an aqueous environment have a predetermined pH dependence. This feature also provides for the retroactive incorporation of bleaching agents or other active agents, such as the loading of the composition with peroxide, peroxyacids, chlorites, stabilizers, flavoring agents, etc. In contrast, the incorporation of a cellulose ester as one of the water-swellable polymers makes the hydrogel sticky before application to a wet surface, but not sticky upon absorption of water. It will be appreciated that said composition may be desirable when a decrease in tackiness is desired for the final removal of the product from the teeth.
2. Water soluble polymers Suitable water soluble polymers include, by way of illustration and not limitation, water soluble cellulose derivative polymers; polyvinyl alcohol; collagen; and polysaccharides of natural occurrence. Examples of water-soluble cellulose-derived polymers include hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydrated cellulose (cellophane) and hydroxypropylmethylcellulose. Examples of naturally occurring polysaccharides include agars of various origins, such as gum agar; alginates such as alginic acid, salts of alginic acid (eg, calcium alginate, potassium alginate, sodium alginate), and alginic acid derivatives (e.g., propylene glycol alginate, Kelcoloid®, Monsanto); carrageenans including kappa, iota and lambda carrageenans; chitin; chitosan; glucomannan; gellan gum (Kelcogel®, Monsanto); jelly; guar gum (TIC gums); gum arabic; ghatti gum; karaya gum; tragacanth gum; carob gum; pectins such as pectin and amylopectin; pullulana; starches and starch derivatives such as potato starch acetate, Clearam® CH10, Roquete; tamarind gum; xanthanes such as xanthan gum; and combinations thereof.
3. Second insoluble polymer in water swellable water The second water insoluble polymer swellable in water is capable of at least some degree of swelling when immersed in an aqueous liquid, but is insoluble in water at all pH values. The second water-swellable water-insoluble polymer can be a cellulosic polymer, a cellulose ester, or an acrylate-based polymer or copolymer, ie, a polymer or copolymer of acrylic acid ester or acrylic acid (an "acrylate" polymer "). The second polymer can also provide some desired adhesion prior to phase separation. For example, when the second polymer is a cellulose ester, the composition is generally sticky before contact with water (eg, with a wet surface), but gradually loses tack as the composition absorbs moisture. When the second polymer is an acrylate polymer or copolymer, a composition is provided which is generally substantially non-tacky before contact with water, but which becomes sticky upon contact with a wet surface. Examples of cellulose esters include, for example, cellulose acetate, cellulose acetate propionate (CAP), cellulose acetate butyrate (CAB), cellulose acetate phthalate, cellulose propionate (CP), cellulose butyrate (CB) ), cellulose butyrate-propionate (CPB), cellulose diacetate (CDA), cellulose triacetate (CTA), or the like. These cellulose esters are described in the U.S. Patents. Nos. 1, 698,049, 1, 683,347, 1, 880,808, 1, 880,560, 1,984,147, 2,129,052 and 3,617,201, and can be prepared using techniques known in the art, or can be obtained commercially. Commercially available cellulose esters, suitable herein, include CA 320, CA 398, CAB 381, CAB 551, CAB 553, CAP 482, CAP 504, all available from Eastman Chemical Company, Kingsport, Tenn. Said cellulose esters typically have a number average molecular weight between about 10,000 and about 75,000. In general, the cellulose ester comprises a mixture of cellulose and monomer units of cellulose ester; for example, commercially available cellulose acetate butyrate contains cellulose acetate monomer units, as well as cellulose butyrate monomer units and non-esterified cellulose monomer units, while cellulose acetate propionate contains monomer units such as propionate cellulose. Preferred cellulose esters herein are cellulose acetate propionate-acetate compositions and cellulose acetate-butyrate compositions having the content of butyryl, propionyl, acetyl and non-esterified cellulose (OH) indicated below:
The preferred molecular weight, glass transition temperature (Tg) and melting temperature (Tm) are also indicated. Also, suitable cellulosic polymers typically have an inherent viscosity (IV) of from about 0.2 to about 3.0 deciliters / gram, preferably from about 1 to about 1.6 deciliters / gram, measured at a temperature of 25 ° C for a sample of 0.5 grams. in 100 ml of a solution at 60/40 by weight of phenol / tetrachloroethane. When prepared using a solvent pouring technique, the water-swellable water-insoluble polymer should be selected to provide greater cohesive strength, and thus facilitate film formation (in general, for example, cellulose acetate propionate tends to to improve cohesive strength to a greater degree than cellulose acetate butyrate). Examples of cellulosic polymers include, for example, methylcellulose and ethylcellulose. Acrylate polymers are also particularly suitable for use as the second water-swellable polymer, and were previously described as the Eudragit® and Kollicoat polymers. However, for use as the second water-swellable polymer, the acrylate polymers are selected to have pH-independent solubility. There are numerous pH-independent polymers in the Eudragit® RL and Eudragit RS series, including RL 30D, RL PO, RL 100, RS 30D, RS PO and RS 100. The Eudragit RL 100 and RS 100 copolymers are particularly well suited for Use as the second water-swellable polymer.
B. Hydrophilic Polymers The second component of the hydrogel composition is a mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and optionally also capable of ionically or covalently binding to the hydrophilic polymer. The hydrophilic polymer is generally a relatively high molecular weight polymer, and the complementary oligomer is generally a lower molecular weight polymer. Suitable hydrophilic polymers include repeating units derived from an N-vinyllactam monomer, a carboxyvinyl monomer, a vinyl ester monomer, an ester of a carboxyvinyl monomer, a vinyl amide monomer, and / or a hydroxyvinyl monomer . Such polymers include, by way of example, poly (N-vinyl lactams), poly (N-vinyl acrylamides), poly (N-alkyl acrylamides), substituted and unsubstituted methacrylic and acrylic polymers (for example, polyacrylic acids and acids). polymethacrylics), polyvinyl alcohol (PVA), polyvinylamine, copolymers thereof and copolymers with other types of hydrophilic monomers (eg, vinyl acetate). Poly (N-vinyl lactams) useful herein, are preferably non-interlaced homopolymers or copolymers of monomeric units of
N-vinyl lactam, wherein the monomeric units of N-vinyl lactam represent the majority of the total monomer units of a copolymer of poly (N-vinyl lactams). 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. Non-limiting examples of different N-vinyl lactam comonomers useful with monomeric units of N-vinyl lactam include N, N-dimethylacrylamide, acrylic acid, methacrylic acid, hydroxyethyl methacrylate, acrylamide, 2-acrylamido-2-methyl-1 acid -propanesulfonic or its salt, and vinyl acetate. Poly (N-alkyl acrylamides) include, by way of example, poly (methacrylamide) and poly (N-isopropyl acrylamide) (PNIPAM). Polymers of carboxyvinyl monomers are typically formed of 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 , wherein preferred hydrophilic polymers within this class include polyacrylic acid and polymethacrylic acid, with polyacrylic acid being more preferred. Preferred hydrophilic polymers herein are the following: poly (N-vinyl lactams), in particular polyvinylpyrrolidone (PVP) and polyvinylcaprolactam (PVCap); poly (N-vinyl acetamides), in particular polyacetamide per se; polymers of carboxyvinyl monomers, in particular polyacrylic acid and polymethacrylic acid; and copolymers and mixtures 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 about 100,000 to 2,000,000, more typically in the range of about 500,000 to 1,500,000. The oligomer is "complementary" to the hydrophilic polymers, because it is able to form hydrogen bonds with them. Preferably, the complementary oligomer ends with hydroxyl groups, amino groups or carboxyl groups. The oligomer typically has a glass transition temperature Tg in the range of about -100 ° C to about -30 ° C, and a melting temperature Tm of less than about 20 ° C. The oligomer can also be amorphous. The difference between the Tg values of 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 must be compatible, that is, capable of forming a homogeneous mixture exhibiting an individual Tg, intermediate between that of the unmixed components.
C. Complementary Oligomer In general, the complementary oligomer will have a molecular weight on the scale of about 45-800, preferably on the scale of about 45-600. The complementary oligomer is preferably a polyalkylene glycol of low molecular weight (molecular weight of
300-600), such as polyethylene glycol 400, which can also serve as a low molecular weight plasticizer. Alternatively, a different compound can be incorporated as an additional low molecular weight plasticizer, in which case any of the low molecular weight plasticizers described below can be used. In one embodiment of the invention, the complementary oligomer is a low molecular weight or oligomeric complementary plasticizer containing at least two functional groups per molecule, which are capable of hydrogen bonding to the hydrophilic polymer. In some cases, the complementary oligomer can also serve as a low molecular weight plasticizer. Alternatively, a different compound can be incorporated as an additional low molecular weight plasticizer and, if included, would be present as approximately 30 to 35% by weight of the composition. Examples of suitable complementary oligomers include, but are not limited to, low molecular weight polyols (eg, glycerol), monomeric and oligomeric alkylene glycols such as ethylene glycol and propylene glycol, ether alcohols (eg, glycol ethers), carbonic diacids, alkanediols of butanediol to octanediol, including derivatives of polyalkylene glycols terminated by carboxyl and terminated by amino. Preferred herein are polyalkylene glycols, optionally carboxyl terminated, and polyethylene glycol having a molecular weight in the range of about 300-600, is an optimal complementary oligomer. It will be appreciated from the foregoing that an individual compound, for example, a low molecular weight polyalkylene glycol such as polyethylene glycol having a molecular weight in the range of about 300-600, can serve as the complementary oligomer and the low molecular weight plasticizer. As discussed in the patent publication of E.U.A. Do not.
2002/0037977 to Feldstein et al., The ratio of the hydrophilic polymer to the complementary oligomer in the aforementioned mixture affects the adhesive strength and the cohesive force. As explained in the patent application mentioned above, the complementary oligomer decreases the glass transition of the hydrophilic polymer / complementary oligomer mixture to a greater degree than predicted by the Fox equation, which is given by the following equation:
wherein the predicted Tg is the predicted glass transition temperature of the hydrophilic polymer / complementary oligomer mixture, Wp0? is the weight fraction of the hydrophilic polymer in the mixture, Wp? is the weight fraction of the complementary oligomer in the mixture, Tg pol is the glass transition temperature of the hydrophilic polymer, and Tg p? is the glass transition temperature of the complementary oligomer. As also explained in said patent application, an adhesive composition having optimized cohesive and adhesive strength can be prepared from a hydrophilic polymer and a complementary oligomer, selecting the components and their relative amounts, to give a predetermined deviation from the predicted Tg. - In general, to maximize adhesion, the predetermined deviation from the predicted Tg will be the maximum negative deviation, while to minimize adhesion, any negative deviation from the Predicted Tg is minimized. Since the complementary oligomer can by itself act as a plasticizer, it is not necessary in general to incorporate an additional plasticizer. However, the inclusion of an additional low molecular weight plasticizer in the composition is optional and may, in some cases, be advantageous. Suitable low molecular weight plasticizers include: dialkyl phthalates, dicycloalkyl phthalates, diaryl phthalates and mixed alkylaryl phthalates, represented by dimethyl phthalate, diethyl phthalate, dipropyl phthalate, di (2-ethylhexyl) phthalate, phthalate diisopropyl, 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, acetyltriethyl citrate and trihexyl citrate; dialkyl adipates such as dioctyl adipate (DOA); also referred to as bis (2-ethylhexyl) adipate, diethyl adipate, di (2-methylethyl) adipate and dihexyl adipate; dialkyl tartrates such as diethyl tartrate and dibutyl tartrate; dialkyl sebacate such as diethyl sebacate, dipropyl sebacate and dinonyl sebacate; dialkyl succinates such as diethyl succinate and dibutyl succinate; alkyl glycollates, alkyl glycerolates, glycol esters and glycerol esters, such as glycerol diacetate, glycerol triacetate (triacetin), glycerol diacetate monolactate, methyl phthalyl ethyl glycolate, butyl phthalyl butyl glycolate, ethylene glycol diacetate , ethylene glycol dibutyrate, triethylene glycol diacetate, triethylene glycol dibutyrate and triethylene glycol dipropionate; and mixtures thereof. Preferred low molecular weight plasticizers for the continuous hydrophilic phase are triethyl citrate, diethyl phthalate and dioctyl adipate, with dioctyl adipate being more preferred. The properties of the composition of the invention are easily controlled by adjusting one or more parameters during manufacture. For example, the adhesive strength of the composition can be controlled during manufacture to increase, decrease or eliminate adhesion. This can be achieved by varying the type and / or quantity of different components, or by changing the manufacturing mode. Also, with respect to the manufacturing process, compositions that are prepared using a conventional melt extrusion process are generally, but not necessarily, somewhat less sticky than compositions that are prepared using a pour-in-solution technique. In addition, the degree to which the hydrogel composition will swell upon contact with water, can be varied by selecting different water-swellable polymers and, in those compositions containing a continuous hydrophilic phase, adjusting the ratio of the water-swellable insoluble polymers in water to the hydrophilic polymer / complementary plasticizer mixture. These compositions may vary in appearance from clear, transparent to translucent to opaque. In addition, certain compositions can be made to be translucent, by changing the relative amounts of the components in the hydrophilic phase (for example, by decreasing the amount of the cellulose ester), or by changing the manufacturing method (translucent hydrogels are more easily obtained using pouring in solution than melt extrusion). In this way, the translucent composition allows the user to observe the therapeutic or cosmetic procedure (e.g., bleaching) while it is occurring, and determines when the desired effect has been achieved, for example, when the teeth have been sufficiently bleached.
III. Active agents The composition can also include any pharmaceutically active agent useful in the treatment of physiological conditions including the teeth and surrounding tissue, as well as the skin and mucosal tissues. The active agent can be any substance that can be released from the composition, to treat an undesirable physiological condition. Undesirable physiological conditions that include the teeth or surrounding tissue, which are subject to treatment with the present device, include: halitosis; periodontal and oral infections; periodontal lesions; tooth decay or decay; gingivitis; and other periodontal diseases. Such agents would be present in a cosmetically or therapeutically effective amount. These include, by way of example and not limitation, adrenergic agents, adrenocortical steroids, adrenocortical suppressors, alcohol deterrents, aldosterone antagonists, amino acids, ammonia detoxicants, anabolic agents, analeptic agents, analgesic agents, androgenic agents, anesthetic agents, anorexic compounds, anorexic agents, antagonists, anterior pituitary activators and anterior pituitary suppressants, anthelmintic agents, anti-acne agents, anti-adrenergic agents, antiallergic agents, antiamoebic agents, antiandrogenic agents, antianemic agents, antianginal agents, antianxiety agents, antiarthritic agents, antiasthmatic agents , antiatherosclerotic agents, antibacterial agents, antichololing agents, antichollezogenic agents, anticholinergic agents, anticoagulants, anticoccidial agents, anticonvulsants, antidepressants, antidiabetic agents, antidiarrheal agents antidiuretics, antidotes, antidiskinetic agents, antiemetic agents, antiepileptic agents, antiestrogen agents, antifibrinolytic agents, antifungal agents, antiglaucoma agents, antihemophilic agents, antihemophilic factor, antihaemorrhagic agents, antihistaminic agents, antihyperlipidemic agents, antihyperlipoproteinemic agents, antihypertensive agents, antihypertensive agents, antiinfective agents , anti-inflammatory agents, anti-anti-inflammatory agents, antimalarial agents, antimicrobial agents, antimigraine agents, antimitotic agents, antifungal agents, anti-nauseating agents, antineoplastic agents, complementary anticancer enhancing agents, antineutropenic agents, antiobsession agents, antiparasitic agents, antiparkinson drugs, antineukocystic agents, antiproliferative agents , antihypertrophic prostatic drugs, antiprotozoal agents, antipruritics, antipsoriatic agents, antipsi comers, antirheumatic agents, antischistosomiasis agents, antiseborrhoeic agents, antispasmodic agents, antithrombotic agents, antitussive agents, antiulcerative agents, antiurolytic agents, antiviral agents, appetite suppressants, benign prostatic hyperplasia therapeutics, blood glucose regulators, bone resorption inhibitors , bronchodilators, carbonic anhydrase inhibitors, cardiac depressants, cardioprotectors, cardiotonic agents, cardiovascular agents, choleretic agents, cholinergic agents, cholinergic agonists, cholinesterase deactivators, coccidiostatic agents, cognitive adjuvants and cognitive enhancers, depressants, diagnostic aids, diuretics , dopaminergic agents, ectoparasiticides, emetic agents, enzyme inhibitors, estrogens, fibrinolytic agents, free radical oxygen scavengers, gastrointestinal motility agents, glucocorticoids, prin gonaestimulants cipios, hair growth stimulants, haemostatic agents, histamine H2 receptor antagonists, hormones, hypocholesterolemic agents, hypoglycemic agents, hypolipidemic agents, hypotensive agents, HMGCoA reductase inhibitors, immunizing agents, immunomodulators, immune regulators, immunostimulants, immunosuppressants, therapeutic impotence adjuvants, inhibitors, keratolytic agents, LHRH agonists, liver disorders treatments, luteolysin agents, memory adjuvants, mental function enhancers, mood modulators, mucolytics, mucosal protective agents, mydriatic agents, nasal decongestants, neuroleptic agents, neuromuscular blocking agents, neuroprotective agents, NMDA antagonists, non-hormonal sterol derivatives, oxytocic agents, plasminogen activators, platelet activating factor antagonists, platelet aggregation inhibitors , post-apoplexy and post-trauma treatments of the head, enhancers, progestins, prostaglandins, prostatic growth inhibitors, protirotropin agents, psychotropic agents, radioactive agents, regulators, relaxers, distributing agents, scabicides, sclerosing agents before, sedatives, sedative-hypnotic agents, selective adenosine A1 antagonists, serotonin antagonists, serotonin inhibitors, serotonin receptor antagonists, steroids, stimulants, suppressors, synergists, thyroid hormones, thyroid inhibitors, thyromimetic agents, tranquilizers, unstable angina agents, uricosuric agents, vasoconstrictors, vasodilators, vulnerary agents, wound healing agents, xanthine oxidase inhibitors, and the like. In one embodiment, the hydrogel composition described above contains a bleaching agent, and thus acts as a delivery system when applied to the teeth. The release of "charged" bleaching agents in the present hydrogel compositions typically includes water absorption and desorption of the agent by a diffusion mechanism controlled by swelling. Hydrogel compositions containing bleaching agent can be used in a manner similar to that of topical pharmaceutical formulations, for example. Suitable dental bleaching agents include peroxides, metal chlorites, perborates, percarbonates, peroxyacids, and combinations thereof. Suitable peroxide compounds include hydrogen peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof. Preferred peroxides are hydrogen peroxide and carbamide. Other suitable peroxides include organic peroxides including, but not limited to, dialkyl peroxides such as t-butyl peroxide and 2,2 bis (t-butylperoxy) propane, diacyl peroxides such as benzoyl peroxide and acetyl peroxide, peresters such as t-butyl perbenzoate and t-butyl per-2-ethylhexanoate, perdicarbonates such as dicetyl peroxydicarbonate and dicyclohexyl peroxydicarbonate, ketone peroxides such as cyclohexanone peroxide and methyl ethyl ketone peroxide, and hydroperoxides such as eumenohydroperoxide and tert-butyl hydroperoxide. The bleaching agent is preferably a peroxide, such as hydrogen peroxide or carbamide peroxide, and more preferably is hydrogen peroxide. Suitable metal chlorites include calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, and potassium chlorite;
hypochlorite and chlorine dioxide. The preferred chlorite is sodium chlorite. In another embodiment, the pharmaceutically active agent can be, for example, a non-spheroidal / analgesic anti-inflammatory; spheroidal anti-inflammatory agents; local anesthetics; bactericides / disinfectants; antibiotics; antifungals; dental desensitizing agents; anti-aging / anticavity agents of fluoride; anti-dental / anticalculus agents; enzymes that inhibit the formation of plaque, calculus or dental caries; abrasive agents such as pyrophosphates; metal chelators such as tetrasodium salt of ethylenediaminetetraacetic acid; antioxidants such as butylated hydroxyanisole; butylated hydroxytoluene; nutritional supplements for local supply to the teeth and surrounding tissue; etc. Suitable non-spheroidal analgesic / anti-inflammatory agents include acetaminophen; methyl salicylate; monoglycol salicylate; aspirin; mefenamic acid; flufenamic acid; indomethacin; diclofenac; alclofenac; diclofenac sodium; ibuprofen; flurbiprofen; fentizac; bufexamac; piroxicam; phenylbutazone; oxyphenbutazone; clofezone; pentazocine; mepirizole; and thiaramide hydrochloride. Suitable spheroidal antiinflammatory agents include hydrocortisone: prednisolone; dexamethasone; triamcinolone acetonide; Fluocinolone acetonide; hydrocortisone acetate; prednisolone acetate; methylprednisolone; dexamethasone acetate; betamethasone; betamethasone valerate; flumethasone; fluorometholone; budesonide; and beclomethasone dipropionate. Suitable local anesthetics include dibucaine hydrochloride; dibucaine; Lidocaine hydrochloride; lidocaine; benzocaine; 2- (diethylamino) ethyl ester hydrochloride of p-butylaminobenzoic acid; procaine hydrochloride; tetracaine hydrochloride; Chloroprocaine hydrochloride; oxiprocaine hydrochloride; mepivacaine; cocaine hydrochloride; and piperocaine hydrochloride. Suitable bactericides / disinfectants include thimerosal; phenol; thymol; benzalkonium chloride; benzethonium chloride; chlorhexidine; povidone iodide; cetylpyridinium chloride; eugenol and trimethylammonium bromide. Suitable antibiotics include penicillin; methicillin; oxacillin; cephalothin; cephaloridin; erythromycin; lincomycin; tetracycline; Chlortetracycline; oxytetracycline; metacycline; chloramphenicol; Kanamycin; streptomycin; gentamicin; bacitracin; and cycloserine. Suitable antifungal drugs include amphotericin; clotrimazole; econazole nitrate; fluconazole; griseofulvin; Itraconazole; ketoconazole; miconazole; nystatin; Terbinafine hydrochloride; undecenoic acid; and zinc undecenoate. Suitable dental desensitizing agents include potassium nitrate and strontium chloride. Suitable fluoride anti-aging / anti-caking agents include sodium fluoride, potassium fluoride and ammonium fluoride. Additional bleaching agents include anticalculus / antiaircraft agents, including phosphates such as pyrophosphates, polyphosphates, polyphosphonates (for example, 1-hydroxy-1,1-diphosphonate of ethane, 1,1-difluorosphonate of 1-azacycloheptane and diphosphonates of linear alkyl), and salts thereof; linear carboxylic acids; and zinc-sodium citrate; and mixtures thereof. Preferred pyrophosphate salts are the dialkali metal pyrophosphate salts; tetraalkaline metal pyrosophosphate salts; and the hydrated or non-hydrated forms of disodium diacid pyrophosphate (Na2H2P2? 7), tetrasodium pyrophosphate (Na4P2O7) and tetrapotassium pyrosphosphate (K4P2? 7). The pyrophosphate salts are described in more detail in Kirk & Othmer, Encyclopedia of Clinical Technology, third edition, volume 17, Wiley-lnterscience Publishers (1982), the full disclosure of which is hereby incorporated by reference in its entirety. Optionally, the bleaching agents may also include agents that dissolve dental tartar, such as betaines, amine oxides and quaternary compounds, as described in the patent of E.U.A. No 6, 315,991 to Zofchak. Enzyme agents that would act to inhibit the formation of plaque, calculus or dental caries would also be useful in the compositions. The enzymatic agents can be stored together with the bleaching agent, or they can be positioned in a different layer within a multi-layer system as described herein. Suitable enzymes include: proteases that degrade salivary proteins that are absorbed on the tooth surface and form the film, or first layer of the plaque; lipases that destroy bacteria using proteins and lipids that form the structural component of walls and membranes of bacterial cells; dextranases, glucanohydrolases, endoglycosidases and mucinases, which degrade the bacterial skeletal structure that forms a matrix for bacterial adhesion to the tooth; and amylases that prevent the development of stones, breaking the carbohydrate-protein complex that binds to calcium. Preferred enzymes include any of the commercially available proteases; dextranases; glucanohydrolases; endoglycosidases; amylases; mutanases; lipases; mucinases; and compatible mixtures thereof. In some embodiments, an enzymatic bleaching agent may also be used. Optionally, an enzymatic bleaching agent is a peroxidase such that the peroxide is generated in situ. When an antiplaque or enzymatic bleach agent is incorporated into the composition, the composition must be such that the enzyme remains in its active form, for example, the pH must be almost neutral, and the peroxide may be omitted or contained in a separate layer . Nutritional supplements suitable for local delivery to the teeth and surrounding tissue, include vitamins (eg, vitamins C and D, thiamin, riboflavin, calcium pantothenate, niacin, folic acid, nicotinamide, pyridoxine, cyanocobalamin, para-aminobenzoic acid, and bioflavonoids); and minerals (eg, calcium, phosphorus, fluoride, zinc, manganese and potassium); and mixtures thereof. Vitamins and minerals useful in the present invention are described in Drug Facts and Comparisons (loose leaf drug information service), Wolters Kluer Company, St. Louis, Mo., 1997, pp 3-17.
The composition may also include any cosmetically active agent that effects a desired change in the appearance of the surrounding teeth or tissue, or imparts a socially desirable characteristic to the user, such as fresh breath. For example, a cosmetically active agent may be a breath freshener or an agent that whiten or whiten the teeth. Recognizing that in some cultures or in certain segments of western society tooth coloring can be significant or desirable, the cosmetically active agent can also be any agent that imparts a color or dye to the teeth. Additional bleaching agents may be included in the composition. For example, surfactants such as detergents may also be present, and will act in conjunction with the bleaching agents described above, to provide a brighter appearance to the teeth. In any of these embodiments, a tooth whitening composition of the invention preferably includes a peroxide for whitening teeth, and may also include conventional additives such as fillers, preservatives, pH regulators, softeners, thickeners, dyes, pigments, dyes, refringent particles, stabilizers, firmness agents, pharmaceutical agents, breath fresheners or flavoring agents, and permeation enhancers. In embodiments where the adhesion is to be reduced or eliminated, conventional tackifiers can also be used. These additives, and amounts thereof, are selected such that they do not significantly interfere with the desired chemical and physical properties of the dental bleaching composition, or interfere with the delivery of the dental bleaching agent, and can be included in the composition. Such additional ingredients include coloring compounds, food additives, flavors, sweeteners and preservatives. Any natural or synthetic food additive or flavorant, such as those described in Chemicals Used in Food Processing, Pub. No. 1274, National Academy of Sciences, pgs. 63-258 (the complete disclosure of which is incorporated herein by reference). Suitable flavors include wintergreen, mint, spearmint, menthol, fruit flavors, vanilla, cinnamon, spices, flavoring oils and oleoresins, as is known in the art, as well as combinations thereof. The amount of flavoring used is normally a matter of preference, subject to factors such as the type of flavor, individual flavor and desired concentration: Preferably, the composition comprises about 0.1-5% by weight of flavor. Sweeteners useful in the present invention include sucrose, fructose, aspartame, xylitol and saccharin. Preferably, the composition comprises sweeteners in an amount of about 0.001-5.0% by weight. The suitable substrate may be translucent so that the composition is discrete when used. However, the substrate or composition can optionally be colored, so that the composition is easily observed when it is used. Preferably, if coloration is desired, the color will be present in the substrate. For example, the substrate can be colored with bright or vibrant colors that a consumer may find pleasing. The substrate may therefore comprise a coloring compound such as, for example, a dye, pigment or substance that can impart color when added to the material forming the substrate. For example, coloring compounds of the type commonly used with a food, drug or cosmetic in relation to the human body, especially color additives allowed for use in food, which are classified as "certifiable" or "exempt from certification", can be used to color the substrate. The coloring compounds used to color the substrate can be derived from natural sources such as plants, minerals or animals, or they can be counterparts of natural man-made derivatives. Coloring compounds currently certified under the Food Drug & amp;; Cosmetic Act for use in foods and ingested drugs, include dyes such as red number 3 FD &C (sodium salt of tetraiodofluorescein); food red 17 (disodium salt of 6-hydroxy-5-. {(2-methoxy-5-methyl-4-sulfophenyl) azo.} -2-naphthalenesulfonic acid); food yellow 13 (sodium salt of a mixture of the monophosphonic and disulfonic acids of quinophthalone or 2- (2-quinolyl) indanedione); yellow number 5 FD &C (sodium salt of 4-sulfophenylazo-1-p-sulfophenyl-5-hydroxypyrazole-3-carboxylic acid); yellow number 6 FD &C (sodium salt of p-sulfophenylazo-B-naphthol-6-monosulfonate); green number 3 FD &C (disodium salt of 4- { [4- (N-ethyl-p-sulfobenzylamino) -phenyl] - (4-hydroxy-2-sulfonium-phenyl) -methylene.} - [1 - (N-ethyl-Np-sulfobenzyl) -3,5-cyclohexadienimine]; blue number 1 (disodium salt of dibenzyldiethyl diaminotriphenylcarbinol trisulfonic acid anhydride), blue number 2 FD &C (sodium salt of disulfonic acid indigotine); red number 40 FD &C; orange B; and citrus red number 2, and combinations thereof in various proportions Coloring compounds exempt from FDA certification include annatto extract beta-apo-8'-carotenal beta -carotene; beet powder; canthaxanthin; caramel color; carrot oil; cochineal extract (crimson carmine); toasted cotton seed flour, partially defatted and cooked; ferrous gluconate; fruit juice; grape-colored extract; of grape skin (enocianin), red pepper, red pepper oleoresin, riboflavin, saffron, turmeric, oleoresin, a turmeric, vegetable juice; and combinations thereof in various proportions. The form of the coloring compound for use in the composition preferably includes additives in the form of a dye, but may also include lacquer forms which are compatible with the material comprising the substrate. Water-soluble dyes, provided in the form of powders, granules, liquids or other forms for special purposes, may be used in accordance with the present method. Preferably, the "lacquer" or water-insoluble form of the colorant is used to color the substrate. For example, if a suspension of a coloring compound is to be used, an additive in the form of a lacquer can be used. Suitable water-insoluble dye lacquers which are prepared by spreading calcium or aluminum salts of FD &C dyes on alumina, include green lacquer number 1 FD &C, lacquer blue number 2 FD &C, lacquer number 30 FD &C and yellow lacquer number 15 FD &C. Other suitable coloring compounds include non-toxic water insoluble inorganic pigments, such as titanium dioxide; green chromium oxide; pink and blue groceries; and ferric oxides. Said pigments preferably have a particle size in the range of about 5-1000 microns; more preferably about 250-500 microns. The concentration of the coloring compound in the substrate is preferably about 0.05-10% by weight, and is more preferably about 0.1-5% by weight. More than one coloring compound may be present in the substrate, so that multiple colors are imparted therein. These multiple colors can be designed in strips, dots, swirls, or any other design that a consumer may find pleasing. The coloring compound can also be used with other substances that improve appearance, such as gloss particles.
Absorbent fillers that control the degree of hydration when the adhesive is on the tooth surface can be advantageously incorporated. Such fillers may include microcrystalline cellulose, talc, lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide, titanium oxide, magnesium silicate, aluminum magnesium silicate, hydrophobic starch, calcium sulfate, calcium stearate, phosphate calcium, calcium phosphate dihydrate, clays such as laponite, woven and nonwoven paper, and cotton materials. Other suitable fillers are inert, i.e., substantially non-adsorbent and include, for example, polyethylenes, polypropylenes, polyether amide and polyurethane copolymers, polyesters and copolymers of polyester, nylon and rayon. A preferred filler is colloidal silica, for example, Cab-O-Sil® (Cabot Corporation, Boston MA). Preservatives include, by way of example, p-chloro-m-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methyl ester, 4-hydroxybenzoic acid propyl ester, benzalkonium chloride, cetylpyridinium chloride, diacetate. or chlorhexidine gluconate, ethanol and propylene glycol. Compounds useful as pH regulators include, but are not limited to, glycerol pH regulators, citrate pH regulators, borate pH regulators, phosphate pH regulators or citric acid phosphate pH regulators, and may be included also to ensure that the pH of the hydrogel composition is compatible with that of the mouth environment, and does not leach minerals from the surface of the teeth. To optimize bleaching without demineralization of the teeth, calcium and / or fluoride salts may be included in the composition. Suitable softeners include esters of citric acid, such as triethyl citrate or acetyltriethyl citrate, esters of tartaric acid such as dibutyl tartrate, glycerol esters such as glycerol diacetate and glycerol triacetate; esters of phthalic acid, such as dibutyl phthalate and diethyl phthalate; and / or hydrophilic surfactants, preferably hydrophilic nonionic surfactants such as, for example, partial fatty acid esters of sugars, polyethylene glycol fatty acid esters, polyethylene glycol fatty alcohol ethers and polyethylene glycol sorbitan fatty acid esters. Preferred thickeners herein are naturally occurring compounds, or derivatives thereof and include, by way of example: collagen; galactomannans; starches; starch derivatives and hydrolysates; cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose; colloidal silicas; and sugars such as lactose, sucrose, fructose and glucose. Synthetic thickeners such as polyvinyl alcohol, vinyl pyrrolidone-vinyl acetate copolymers, polyethylene glycols and polypropylene glycols can also be used. The substrate may also be included or decorated with decorative articles such as beads, false stones, or the like, as long as these articles do not interfere with the viscoelastic properties of the substrate required for adequate deformation of the composition on the teeth, as described above. The substrate may also display letters, words or images designed to be pleasing or attractive to the consumer.
IV. Manufacturing processes The compositions of the invention are generally melt extrudable, and can thus be prepared using a simple mixing and extrusion process. The components of the composition are then weighed and mixed, for example, using a Brabender or Baker Perkins mixer, generally but not necessarily, at an elevated temperature, for example, about 90-140 ° C. Solvents or water may be added, if desired. The resulting composition can be exempted using a single worm or twinworm extruder, or it can be transformed into pellets. Alternatively, the components of the composition may be fused one at a time, and may then be mixed prior to extrusion. Preferably, the composition is extruded directly onto a suitable substrate such as a reinforcing layer or a release liner, and can then be pressed. The thickness of the resulting hydrogel-containing film, for most purposes, will be on the scale of about 0.050-0.80 mm, more usually on the scale of about 0.37-0.47 mm. Alternatively, the compositions can be prepared by pouring into solution, mixing the components of the composition in a suitable solvent; for example, a volatile solvent such as ethyl acetate, or lower alkanols (e.g., ethanol, isopropyl alcohol, etc.), is particularly preferred, at a concentration typically in the range of about 35-60% w / v. The solution is poured onto a suitable substrate such as a reinforcement layer or release liner, as indicated above. Both mixing and pouring are preferably carried out at room temperature. The substrate coated with the film is then baked at a temperature in the range of about 80-100 ° C, optimally at about 90 ° C, for a period in the scale of about one to four hours, optimally about two hours. Accordingly, one embodiment of the invention is a method for preparing a hydrogel film suitable for incorporation into a composition of the invention, which includes the following steps: preparing a solution of an insoluble polymer in water swellable in water or a soluble polymer in water, a hydrophilic polymer, a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and a second polymer insoluble in water swellable in water, 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 80-100 ° C for a period in the range of about 1-4 hours, thereby providing a hydrogel film on the substrate. When sticky hydrogel compositions are desired, melt extrusion is the preferred method, although pouring into solution can still be used. For the preparation of substantially non-tacky compositions, pouring into solution is preferred. Also, the melt extrusion process can be used for any of the compositions of the invention. Also, solution pouring or melt extrusion techniques can be used to prepare translucent compositions, although solution pouring is typically preferred for these embodiments. Accordingly, another embodiment of the invention is a method for forming a composition, which includes the following steps: melt processing through an extruder a mixture of a water-insoluble water-swellable polymer or a water-soluble polymer, a polymer hydrophilic, a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer, and a water insoluble second water swellable polymer, to form an extruded composition; extruding the composition as a film of desired thickness onto a suitable substrate; and, when cool, load the film with an aqueous solution of the active agent such as a peroxide, to obtain a bleaching agent concentration of about 1-20% by weight. The invention also contemplates having a multiple layer system that includes one or more layers of hydrogel or no additional hydrogel. For example, it may be desirable to include additional active agents that may not be compatible with the primary active agent during storage. In this way, one layer may be the hydrogel layer containing the primary active agent, and the other layer or the other layers may contain additional active ingredients. These other layers may be formed from the hydrogel composition described herein, or any other biocompatible formulation known in the art (eg, polyisobutylene, dimethyl siloxane, ethylene vinyl acetate, polyvinyl acetate, cellulose acetate, butyrate or propionate, ethyl cellulose and insoluble acrylates in water). In addition, depending on the order of the layers, it may be desirable to have a sticky layer, for example, the layer to be positioned directly on the teeth, and a non-tacky layer, for example, the outer layer which is positioned closer to the surface. the lips. Another advantage of having a multi-layer system is that the ratio of polymers used in the outermost layer can be varied to obtain non-tacky layers which avoid having to include a separate reinforcing layer in the product. In one embodiment, the composition comprises: an exterior substrate that serves as an exterior surface of the composition after application to the tooth, oral tissue, skin or mucosal surface; an adhesive layer in contact with the surface adhered thereto, which will generally be an adhesive composition of the invention optionally containing additional active agents; and a removable release liner. After removal of a release liner, for example, the composition is applied to the surface, for example, the teeth to be treated, and placed on the surface, so that the layer that is in contact with the Oral surface is in contact. In another embodiment, the composition is packaged without a reinforcement layer or a release liner. Therefore, once removed from the package, the composition is ready to be applied to the surface of the body. The substrate is the primary structural element, and provides the composition with support, either during manufacture or during use. The material used for the substrate must be inert and unable to absorb the hydrogel composition. Also, the material used for the substrate should allow the device to follow the contours of the teeth or other surface of the body, and be used comfortably in the mouth without rubbing or otherwise irritating the lips or tongue. Examples of materials useful for the substrate are polyesters, polyethylene, polypropylene, polyurethanes and polyether amides. The substrate is preferably in the range of about 15 to 250 microns thick and may, if desired, be pigmented, metallized or provided with a matte finish suitable for writing. In one embodiment, the substrate is preferably, but not necessarily, occlusive (ie, not "breathable"), and does not allow any active agent in the composition to come out through the layer, and come in contact with the mucous membranes of the mouth and gums. When ready for use, the composition is pre-moistened so that the tack increases, and the composition adheres to the teeth. An advantage of this embodiment is that the active agent can not escape substantially through the substrate and cause irritation in those individuals sensitive to the active agent, or any unpleasant taste or sensation. Other suitable substrate materials can be non-polymeric materials such as waxes (e.g., microcrystalline waxes or paraffin waxes) or a foam / wax laminate. Paraffin waxes are straight-chain hydrocarbons of low molecular weight, with melting points of about 48-75 ° C and molecular weights of about 300-1400 g / mol, and are typically produced by Fischer-Tropsch synthesis. Microcrystalline waxes are flexible and amorphous in appearance, and tend to have higher tensile strength and smaller crystal size than paraffin waxes. The microcrystalline waxes typically have melting points of about 60-95 ° C and molecular weights of about 580-700 g / mol, and contain predominantly branched chain hydrocarbons and some ring-like compounds, although straight-chain hydrocarbons may be present. The substrate material can also be an open cell foam, such as a polyurethane, polystyrene or polyethylene foam. Alternatively, in another embodiment, the substrate is non-occlusive, and therefore can be fully hydrated in situ, in position on the teeth or other surface of the body. The release liner is a disposable element that serves to protect the system before application. The release liner should be formed of a material impermeable to the active agent and hydrogel composition, and easily stripped of the contact adhesive. The release liners are typically treated with silicone or fluorocarbons, and are commonly made of polyesters and polyethylene terephthalate. A preferred composition is typically prepared using acrylate polymers such as the first and second water-insoluble water-swellable polymers; and a mixture of polyvinylpyrrolidone and polyethylene glycol as the mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer. An adhesive film of the composition can be made by thermally melting and mixing the above components together at temperatures ranging from about 100-170 ° C. The film is extruded to a desired thickness on a suitable substrate. In alternative form, the components can be dissolved in an individual solvent or mixture of solvents, and the solution can be poured onto a reinforcing or release film. The solvents are then evaporated to obtain a hydrogel film. A method for loading the composition with the active agent comprises stratifying a desired active agent, for example, a dental bleaching agent, in aqueous solution on the surface of the hydrogel placed on a suitable substrate, or placing the active agent directly on the substrate . The release liner is then assembled on top of the composition, forming a sandwich structure, and the solution containing the bleaching agent is absorbed into the composition due to its water-swellable properties. Alternatively, the stratified composition on the substrate can be immersed in a solution containing the desired concentration of bleaching agent, and the solution is absorbed into the composition. When measuring the rate of weight gain during the absorption of the liquid, the percent charge of the composition with the active agent can be determined and controlled. Another method for loading the active agent into the composition is to add the active agent as a solid or as a solution to the composition dissolved in solvent. The mixture is then poured as usual onto a suitable substrate, and allowed to dry, although a lower drying temperature is desired when this charging method is used. Compositions prepared in this way can be dried at room temperature for a period ranging from about 1 hour to several days. A typical thickness of the film is about 0.050-0.80 mm, preferably 0.25-0.50 mm. The thickness of the film is not critical, and can be varied according to the concentration of bleaching agent incorporated in the film, the duration in which the film is to be exposed to the teeth, the level of comfort desired by the user, and the degree of staining that you want to rectify.
V. Methods of use In practice, compositions can be used simply by removing the product from its packaging, removing a release liner.
(when included), and applying the adhesive layer to the teeth you want to whiten (or any surface of the body, skin or mucosa if you are going to have another use of the bleaching agent, or if you are going to use another agent active). The systems described herein can be provided in a variety of sizes, so that the composition can be applied to all or any portion of a tooth, to any number of teeth at a time, or to any portion of the oral cavity. The substrate, when occlusive, reduces or prevents the loss of the active agent, of the composition, while the user uses the composition for the desired amount of time. The composition can be maintained at the desired site for as little as a few minutes, several ho all day or during the night, and can then be removed when the desired degree of whiteness or the desired therapeutic or cosmetic effect has been achieved. If desired, a translucent composition can be provided, and used without being obtrusive or noticeable by others. The system can also be designed without an active ingredient, and finds utility as a protective dressing for an oral surface, e.g., labial fire, cold sores, etc., or as a dressing. The composition can be used for an extended period, but will typically be used for a predetermined period of from about 10 minutes to about 24 ho For dental bleaching applications, a preferred period is from about 10 minutes to about 8 ho(e.g., overnight), also being a preferred mode from 30 minutes to about 1 hour. For other active agents, a therapeutically or cosmetically effective time can be easily determined based on the active agent being used, as well as the condition being treated. A user may form the composition around the upper or lower teeth or other tissue of the oral cavity by applying normal manual pressure to the substrate with the fingertip and thumbs, optionally wetting the composition before application. Assuming the surface area of the tip of the thumb or finger average adult is about one square centimeter, the normal pressure generated by the finger or thumb is approximately 100,000-150,000 Pascals (ie, approximately 1.36 kg) per square centimeter. The pressure is typically applied to the composition by the yolk of each finger or thumb for approximately one or two seconds. Once the pressure applied to the substrate is removed by the fingertip and thumbs, the composition remains in the form of, and adherent to, the surface of the teeth and the attached soft tissue upon which it was formed. When the user is ready to remove the composition, the composition can be removed simply by detaching it from the surface of the teeth or other oral or body surface. If desired, the composition can be re-adhered for additional treatment time. Any remaining residue is minimal, and can be removed using conventional methods of dental cleaning or oral cavity. In one embodiment of the invention, the composition is a solid, and is a pressure sensitive adhesive and absorbs water. This can be achieved by manufacturing the composition that forms phase separation film prior to application to the body surface. The solid formulations obtained in this way could then be packaged and removed from the package before use. The composition is preferably applied as a non-solid composition, for example, applied as a liquid or gel. For example, the user can extrude the composition of a tube on a finger for application to the teeth or other surface of the body, extrude the composition of a tube directly on the teeth, apply the composition by means of a toothbrush or other applicator, etc. After evaporation of the solvent, the liquid or gel composition is dried to form a matrix polymer gel or film on the surface of the body. In one embodiment of this liquid or gel composition that forms a film, the hydrogel contains sufficient water or another solvent to provide a fluid property. In another embodiment of this composition, the polymer components of the liquid or gel composition are soluble in a water-ethanol mixture at room temperature and at refrigeration temperatures of about 4 ° C, and are miscible upon evaporation of the solvent. In another embodiment of this film-forming liquid or gel composition, the polymer composition has a lower critical solution temperature of about 36 ° C in an ethanol-water mixture. The resulting film (after evaporation of the solvent) is preferably insoluble or slowly soluble in the saliva at body temperature, to provide long-lasting contact between hydrogen peroxide and tooth enamel.
Finally, the hydrogen peroxide must be stable in the liquid or gel composition, as well as within the polymeric film after drying. The practice of the present invention will use, unless otherwise indicated, conventional techniques of polymer chemistry, adhesive manufacture and hydrogel preparation, which are within the skill of the art. These techniques are explained in detail in the literature. It will be understood that while the invention has been described in conjunction with the preferred specific embodiments thereof, the foregoing description, as well as the following examples, are intended to illustrate and not to limit the scope of the invention. Other aspects, advantages and modifications will be apparent to those skilled in the art to which the invention pertains. The following examples are set forth to provide those skilled in the art with a complete description of how to obtain and use the compounds of the invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure accuracy with respect to figures (eg, quantities, temperatures, etc.), but some errors and deviations must be accounted for. Unless stated otherwise, the parts are parts by weight, the temperature is in degrees Celsius (° C), and the pressure is at atmospheric pressure or near atmospheric pressure. The following abbreviations and trademarks are used in the examples:
Eudragit L 100-55 Methacrylic acid copolymer (Rohm America Inc.)
PEG polyethylene glycol 400 PVP30 Polyvinylpyrrolidone Plasdone® K30 (ISP) PVP90 Polyvinylpyrrolidone Kollidon® 90F (BASF)
EXAMPLES
EXAMPLE 1 Preparation of a solid composition
An embodiment of a bleaching composition was prepared
dental, from the following ingredients using a procedure of
Melt extrusion:
Eudragit L 100-55 9% by weight PVP90 44% by weight PEG 22% by weight Hydrogen peroxide 6% by weight Water, stabilizers, 19% by weight pH modulators
The ingredients were processed by melting in an extruder of a
only Brabender worm, as follows: Eudragit L 100-55 was added first to the extruder, followed by PVP90 and PEG, at a temperature of 100 to 150CC. The composition was extruded to a thickness of 0.35 mm between two polyethylene terephthalate release liners. Hydrogen peroxide solution was added to the extruded film.
EXAMPLE 2 In vitro release of hydrogen peroxide from a solid composition
The release of hydrogen peroxide from the dental bleaching compositions of the invention was investigated in vitro, at pH 7.0 regulator, and compared to that of the peroxide released from a commercial product, Whitestrips ™ Crest (a product of The Procter & Gamble Co., Cincinnati, OH, and referred to as the "Crest product"). The Crest product contains 5.3% hydrogen peroxide on a Carbopol 956 gel on a thin polyethylene film. The in vitro release of hydrogen peroxide from the compositions containing 3%, 6% or 9% peroxide (formulated as set out in example 1) was compared with the release of hydrogen peroxide from the Crest product. The test composition or the Crest product was allowed to release peroxide in the solution through filter paper, and the peroxide was measured using standard analytical techniques. For the Crest product, the observed peroxide levels decreased to baseline within approximately 30 minutes. These data are similar to the published data (Pagel, PA, ef al. (2000) Vital Tooth Whitening with a Novel Hydrogen Peroxide Strip System: Design, Kinetics, and Clinical Response, Compendium, Suppl 29, Vol. 21: S10- S15). The dental bleaching compositions of the invention released peroxide at a rate proportional to the starting concentration. It was also found that the compositions of the invention release peroxide at a higher rate than the Crest product at all times when the peroxide content was tested:, 30 and 60 minutes. The peroxide release for the composition containing 6% peroxide, which is close to that of the Crest product, was approximately 7.5, 24 and 10 times greater than the rate of release for the Crest product at each time point, respectively. The peroxide release for the composition containing 3% peroxide was about 3, 7 and 5 times higher than the rate of release for the Crest product at each time point, respectively.EXAMPLE 3 Efficacy of a solid composition
The effectiveness of dental bleaching compositions was tested, using the following procedure. One subject tested the efficacy of the dental bleaching composition prepared according to the procedure described in example 1, applying the composition to the lower group of teeth once a day for 1 hour, for 6 consecutive days. The shade of the subject's teeth was measured using the Professional Tooth Shade Guide before and after the treatment of teeth with the dental bleaching composition. On day 1, the subject's teeth received the nuance rating of 12, and after one hour of treatment with the tooth whitening composition, the teeth received the nuance rating of
. After one hour of treatment with the bleaching composition
dental on day 2, the subject's teeth received the nuance rating of 8.
After one hour of treatment on day 3, the subject's teeth
received the qualification nuance of 5. Also, after one hour of
treatment on day 4, the subject's teeth received the nuance rating of 4/5. On day 5, after one hour of treatment, the subject's teeth received the nuance rating of 2/3. The lightest shade was achieved after another half hour of treatment on day 6, reaching a hue of 2. In this way, the effectiveness of the dental bleaching composition was evident, with measurable results within one hour of treatment.
EXAMPLE 4 Preparation of a non-solid composition
A composition for dental bleaching was prepared, starting from
following ingredients (formula A):
Deionized water 35.0% by weight Ethanol 35.0% by weight Eudragit L 100-55 4.00% by weight PEG 1.00% by weight PVP90 7.00% by weight Carbamide peroxide 18.0% by weight Sodium citrate 0.13% by weight
The composition was mixed in a Cole-Parmer high torque low speed laboratory mixer provided with Teflon coated impeller (5.08 cm diameter), as follows. Deionized water was mixed with ethanol, followed by the addition of PEG. Sodium citrate was then added under vigorous stirring conditions. Eudragit L 100-55 powder was added slowly (within 2-5 minutes) under vigorous stirring (500-600 rpm). After approximately 5-10 minutes (it is not necessary to wait until the Eudragit dissolves), PVP90 powder was added slowly (within 5 minutes). The high stirring speed was maintained for 5 to 10 minutes. Powdered carbamide peroxide (within 1-2 minutes) was added, and the mixture was stirred until a homogeneous solution was obtained (approximately 30 minutes at 800-900 rpm). The solution was then stored for a period of 2 to 5 hours, to allow the air bubbles to dissipate.
EXAMPLE 5
Preparation of a non-solid composition
A composition for dental bleaching was prepared, starting from
following ingredients (formula B): Deionized water 35.0% by weight Ethanol 35.0% by weight Eudragit L 100-55 2.50% by weight PEG 1.92% by weight PVP90 6.00% by weight Carbamide peroxide 18.0% by weight 0.08% sodium citrate Weight Methocel A4C 1.50% by weight
The composition was mixed in a Cole-Parmer high torque low speed laboratory mixer provided with Teflon coated impeller (5.08 cm diameter). Deionized water was mixed with ethanol, followed by the addition of PEG. Sodium citrate was then added under vigorous stirring conditions. Eudragit L 100-55 powder was added slowly (within 5 minutes) under vigorous stirring (500-600 rpm),
followed by the slow addition (within 5 minutes) of Methocel A4C powder
under vigorous stirring (500-600 rpm). After about 10 minutes, PVP90 powder was slowly added (within 5 minutes). The high stirring speed was maintained for 5 to 10 minutes. Carbamide peroxide powder was added (within 1-2 minutes), and the mixture was stirred
until obtaining a homogeneous solution (approximately 30-60 minutes at 500-800 rpm). The solution was then stored for a period of 2 to 5 hours, to allow the air bubbles to dissipate.
EXAMPLE 6 Comparative study of in vitro dissolution for non-solid compositions
The dissolution of the non-solid dental bleaching compositions prepared according to the procedure described in Examples 4 (formula A) and 5 (formula B) was compared with the solution of a commercial product, clear whitening gel Simply White® (a product of Colgate-Palmolive Company, New York, NY, and referred to as the "Colgate product"), which contains 18.0% by weight of carbamide peroxide. The dissolution procedure was studied by the wedge microinterferometry technique. It was found that formula A forms an acute phase boundary that separates the swollen polymer composition from the polymer solution. At the phase boundary, an acute decrease in the polymer concentration (and hence the viscosity of the polymer) was observed. No such limit was found in the Colgate water / product interdiffusion zone, whose interference pattern was typical of a completely miscible system with a uniform decrease in polymer concentration (and hence polymer viscosity) in the direction from the matrix of the composition to the water. It was found that formula B has a heterogeneous (colloidal) nature. An acute phase boundary formed between the opaque gel and the translucent aqueous solution. It was also found that formula B has "faster dissolution" fractions and "slower dissolution" fractions. The slower dissolution fractions formed a relatively thin layer that encompassed the heterogeneous opaque swollen gel. Contrary to the Colgate product, formula A and B after contact with aqueous media are capable of forming a continuous integrated viscous swollen gel coating separated from a liquid solution by an acute phase boundary. Phase limit formation for formula A and B was observed in aqueous media with different pH values ranging from 4. 6 to 7.5. By using formulas A and B, an acute phase boundary separates the swollen polymer from the polymer solution. There is no such limit in the Colgate-water product interdiffusion zone whose interference pattern is typical of the system complements miscible with a uniform decrease in polymer concentration (and hence the viscosity of the polymer) in the direction of the formula matrix A and the matrix of formula B towards water. The effective mass transfer constants of water in formula A or B and formula A or B in water are comparable for the Colgate product and formulas A and B. However, contrary to the Colgate product, in the case of the product formation of the acute phase boundary, separation of the swollen integrated gel from the liquid aqueous solution is observed. The effective diffusion coefficient of the phase boundary is 1 to 2 orders less than that of water in formula A or B and formula A or B in water. The swollen gel layer formed by the formulas A and B in the aqueous medium is capable of performing a protective coating function with sustained dissolution rate. The swollen gel also provides a mechanical support that increases the residence time of formulas A and B on the surface of the teeth. The kinetics of the penetration of the composition in water was practically identical for the formulas A and B, while the kinetics of the displacement of the phase limit was lower for the formula B. The constants of effective mass transfer were comparable for the product Colgate and for formulas A and B. However, in the case of formulas A and B, an acute phase boundary separating the swollen integrated gel from the liquid solution was observed. Under conditions of actual use, the erosion of formulas A and B (and therefore their time of use) depended almost mainly on two factors: 1) free interdiffusion procedures of the composition and water (saliva), and 2) random mechanical shear stresses imposed on the coating during the time of use (i.e., friction caused by the movement of the lips). The first factor can be considered as an ideal limitative (undisturbed) process, while the latter can affect the duration of use in a dramatic and random way, since each event of rupture of the coating dramatically changes the initial interdiffusion conditions (ie , thickness of the coating and ingredients of the composition). Preliminary use studies indicated that Formulas A and B are able to remain on the teeth for more than 10 to 15 minutes, while it was found that the Colgate product remains on the teeth for more than 2 to 3 minutes.
EXAMPLE 7 Comparative in vitro efficacy for non-solid compositions
The in vitro efficacy of the non-solid dental bleaching composition prepared according to the procedure described in example 4 (formula A) was compared with the dissolution of the Colgate product. A composition of formula A and the Colgate product were applied on a tea-stained wall of a cup, to demonstrate a "first" treatment. After 30 seconds, water was introduced into the cup to cover the coated surface. After 30 minutes, the water was removed, and the cup was rinsed with water to remove any remaining gel coating on the wall. The experiment was repeated by applying each composition on the same spot to demonstrate a "second" treatment. The images of the treated areas were captured by digital camera, and the images obtained were converted into gray scale images of 250 pixels, using the Scion Image software. The images were scaled up, so that a value of 1 pixel corresponded to an absolute white color, and a value of 256 corresponded to an absolute dark color. The values of intermediate pixels (from 2 to 255) correspond in this way to intermediate colors, increasing the darkness from 1 to 256. The Scion Image software was also used to measure the density
color (pxl / pxl2) of the treated areas. The results, shown below, show that the composition of the formula whitens better
than the Colgate product commercially available. The highest standard deviation observed for formula A, is explained by less uniformity
of the initial color of the tea stain.
Average density (pxl / pxl2) (standard deviation). ,,. After the After. n is . first second tra.am.ento tra?
Product 194.3 (3.8) 185.7 (6.2) 178.0 (6.6)
Colgate Formula A 198.3 (5.2) 178.6 (8.2) 167.6 (9.0)
This experiment was repeated using the non-solid dental bleaching composition prepared according to the procedure described in the example
(formula B), except that only a "first" treatment was done.
Average density (pxl / pxl2) (standard deviation) Before treatment DesPuf s of the first treatment Colgate product 116.9 (6.6) 89.4 (6.79) Formula B 117.3 (5.1) 79.6 (7.3)
As can be seen from the in vitro data presented
above, the bleaching efficiency of the composition of formula A is appreciably higher than that of the Colgate product, and the properties of the
The composition of formula B are intermediate between those of the Colgate product and formula A.
EXAMPLE 8
In vitro release of hydrogen peroxide from a non-solid composition
The release of hydrogen peroxide from the non-solid dental bleaching composition of Example 4 (formula A) was compared with the
dissolution of the Colgate product. The Colgate product was poured onto a release liner, and dried at room temperature for one day. The movies
obtained from the Colgate product, approximately 300-400 μ in thickness,
were placed in a glass beaker, and 200 ml of
deionized water. The composition of formula A was poured on the bottom of a
beaker. After 2 to 3 minutes, 200 ml of deionized water was added. After a suitable period, the solution separated with
accuracy of the swollen residue, and the concentration of peroxide was determined
of hydrogen according to the titration method of the United States Pharmacopoeia. The amount of hydrogen peroxide released from the Colgate product and formula A, is shown below:
Percentage (w / w) of hydrogen peroxide released
Time 1 2 3 5 10 15 20 30
(minutes) Product ___ 38 ___ 47 and 72 4 78J g6 8 ___
Colgate Formula A 35.0 35.9 59.5 67.5 71.9 - 79.2 90.0 In contrast to the Colgate product, the hydrogen peroxide release profile of the film formed by formula A was sustained and characterized by an accelerated supply of the active agent within the first five minutes. After 10 minutes of contact with water, formula A released less hydrogen peroxide than the Colgate product. After 20 minutes of contact with water, the Colgate product did not contain hydrogen peroxide, while formula A contained 20% of the hydrogen peroxide initially charged. This was evidence of stronger binding of hydrogen peroxide to the polymers in formula A than in the Colgate product. By comparing the release and dissolution data of the film, it was also concluded that the content of hydrogen peroxide incorporated in the film of formula A could be categorized as loosely bound hydrogen peroxide or tightly bound hydrogen peroxide. This contrasted with the Colgate product, where all the hydrogen peroxide was loosely bound.
EXAMPLE 9 Comparative in vivo efficacy of non-solid compositions
The in vivo efficacy of the non-solid dental bleaching composition of formula A and formula B was compared with the dissolution of the Colgate product. The bleaching efficiency of formula A and formula B was compared with that of the Colgate product, using the scale oriented towards guide values of Vita shades. The study was a randomized, parallel-group, double-blind pilot study. Eleven subjects were recruited with a scale oriented towards the values of the Vita nuance guide of A3 or darker in a minimum of four of the six anterior maxillary teeth, to participate in the study. The 11 subjects were randomly assigned to one of the three treatment groups based on the Vita shade guide of the maxillary central incisors. The subjects received sufficient product for 14 days of use, and were instructed to use the product twice a day for two weeks. Based on the evaluations with the Vita nuances guide and interviews with the subject, it was evident that formula A, formula B and the Colgate product provided a statistically significant bleaching effect from the seventh day of treatment. The best bleaching effect was observed for formula A. Formula B showed a bleaching effect that was intermediate between that of formula A and the Colgate product. Formula A demonstrated a faster tooth whitening effect compared to the Colgate product.
EXAMPLE 10 Preparation of a non-solid phase separation composition
A composition for dental whitening was prepared, from the following ingredients:
Eudragit L 100-55 6.99 g PVP30 14.97 g PVP90 4.49 g Water 25.95 g Ethanol (95%) 28.94 g PEG 3.99 g Eudragit RL 100 4.49 g Sodium citrate 0.20 g Hydrogen peroxide 9.98 g
The composition was mixed in a laboratory mixer of
Low speed high torque Cole-Parmer provided with an impeller
Teflon coated (5.08 cm diameter), as follows. It was mixed
PEG with ethanol. Eudragit RL 100 was dissolved in the ethanol-PEG mixture, followed by the addition of Eudragit L 100-55. Sodium citrate was then added with stirring. Water was then added to the mixture, followed by hydrogen peroxide and then PVP90 followed by PVP30, and allowed to mix for 2 hours. The solution was then stored for a period of 2 to 5 hours, to allow the air bubbles to dissipate.
EXAMPLE 11 Preparation of a non-solid phase separation composition
A composition for dental bleaching was prepared from the following ingredients, and mixed as described in Example 9:
Eudragit L 100-55 4.99 g PVP30 12.97 g PVP90 2.50 g Water 23.95 g Ethanol (95%) 26.95 g PEG 7.98 g Eudragit RL 100 2.50 g Sodium citrate 0.20 g Carbamide peroxide 17.96 g
EXAMPLE 12 In vitro release of hydrogen peroxide from a non-solid phase separation composition
Experiments were carried out in a manner similar to that set forth in example 2, to evaluate the in vitro release of peroxide from the dental bleaching compositions of examples 10 and 11. It was found that the formulations of examples 10 and 11 provide relatively more sustained release of peroxide, compared to a similar formulation that did not contain Eudragit RL-100. The formulations of Examples 10 and 11 also provided a more sustained profile compared to Colgate's Simply White® product.
Claims (44)
1. - A phase separation film formation composition, comprising: (a) a first water swellable polymer, said polymer being insoluble in water at a pH of less than about 5.5, or a water soluble polymer; (b) a mixture of a hydrophilic polymer and a complementary oligomer capable of hydrogen bonding to the hydrophilic polymer; (c) a second polymer swellable in water, said polymer being insoluble in water at all pH values; and (d) an optional active agent.
2. The composition according to claim 1, further characterized in that the first polymer insoluble in water swellable in water is a polymer or copolymer based on acrylate.
3. The composition according to claim 2, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate or ethyl methacrylate. .
4. The composition according to claim 3, further characterized in that the acrylate-based copolymer is a copolymer of methacrylic acid and methyl methacrylate.
5. The composition according to claim 1, further characterized in that the water-soluble polymer is selected from water-soluble cellulose-derived polymers; polyvinyl alcohol; collagen; and polysaccharides of natural occurrence.
6. The composition according to claim 1, further characterized in that the second polymer insoluble in water swellable in water is a cellulose ester or a polymer or copolymer based on acrylate.
7. The composition according to claim 6, further characterized in that the cellulose ester comprises at least one cellulosic polymer containing unesterified cellulose monomer units, cellulose acetate monomer units, and monomer units of cellulose butyrate or monomeric units of cellulose propionate.
8. The composition according to claim 6, further characterized in that the acrylate-based polymer or copolymer is selected from polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate or ethyl methacrylate. .
9. The composition according to claim 8, further characterized in that the acrylate-based copolymer is a copolymer of methacrylic acid and methyl methacrylate.
10. The composition according to claim 1, further characterized in that the weight ratio of the water-swellable, water-insoluble first polymer to the water-swellable, water-insoluble second polymer is within the range of about 1: 3 to 3. :1.
11. The composition according to claim 10, further characterized in that the ratio is within the range of about 1.5: 1 to 2: 1.
12. The composition according to claim 1, further characterized in that the hydrophilic polymer is selected from the group consisting of poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), polyacrylic acids , polymethacrylic acids, polyvinyl alcohol, polyvinylamine, and copolymers and mixtures thereof.
13. The composition according to claim 12, further characterized in that the hydrophilic polymer is selected from the group consisting of poly (N-vinyl lactams), poly (N-vinyl amides), poly (N-alkyl acrylamides), and copolymers and mixtures thereof.
14. The composition according to claim 13, further characterized in that the hydrophilic polymer is a poly (N-vinyl lactam) or a homopolymer of poly (N-vinyl lactam).
15. The composition according to claim 12, further characterized in that the poly (N-vinyl lactam) is selected from the group consisting of polyvinylpyrrolidone, polyvinylcaprolactam, and mixtures thereof.
16. The composition according to claim 15, further characterized in that the poly (N-vinyl lactam) is polyvinylpyrrolidone.
17. The composition according to claim 12, further characterized in that the hydrophilic polymer has a number-average molecular weight on the scale of about 10,000 to 2,000,000.
18. The composition according to claim 1, further characterized in that the complementary oligomer has a molecular weight in the range of about 45 to 800.
19. The composition according to claim 18, further characterized in that the complementary oligomer has a molecular weight on the scale of about 45 to 600.
20. The composition according to claim 18, further characterized in that the complementary oligomer is selected from the group consisting of polyalcohols monomeric and oligomeric alkylene glycols, polyalkylene glycols, polyalkylene glycols terminated by carboxyl, amino-terminated polyalkylene glycols, ether alcohols, alkanediols and carbonic diacids.
21. The composition according to claim 20, further characterized in that the complementary oligomer is selected from the group consisting of polyalkylene glycols and polyalkylene glycols terminated in carboxyl.
22. The composition according to claim 21, further characterized in that the complementary oligomer is selected from the group consisting of polyethylene glycol and carboxyl-terminated polyethylene glycol.
23. The composition according to claim 21, further characterized in that the complementary oligomer is polyethylene glycol.
24. - The composition according to claim 1, further characterized in that the active agent is present, and is a bleaching agent selected from the group consisting of peroxides, metal chlorites, perborates, percarbonates, peroxyacids, and combinations thereof.
25. The composition according to claim 24, further characterized in that the peroxide is selected from the group consisting of hydrogen peroxide, calcium peroxide, carbamide peroxide, and mixtures thereof.
26. The composition according to claim 25, further characterized in that the peroxide is selected from the group consisting of dialkyl peroxides, diacyl peroxides, peresters, pericarbonates, ketone peroxides and hydroperoxides.
27. The composition according to claim 24, further characterized in that the metal chlorite is selected from the group consisting of calcium chlorite, barium chlorite, magnesium chlorite, lithium chlorite, sodium chlorite, potassium chlorite, hypochlorite and chlorine dioxide.
28. The composition according to claim 1, further characterized in that it comprises at least one additive selected from the group consisting of flavorings, sweeteners, fillers, preservatives, pH regulators, softeners, thickeners, dyes, pigments, dyes, particles refringents, flavorings, sweeteners, stabilizers, firmness agents, tackifiers and permeation enhancers.
29. The composition according to claim 1, further characterized in that the relative amounts of the first and second water-swellable polymers, the hydrophilic polymer and the complementary oligomer, are selected to make the composition translucent.
30. The composition according to claim 1, further characterized in that it comprises approximately 0.1-60% by weight of an active agent.
The composition according to claim 1, further characterized in that it comprises approximately 0.1-20% by weight of the first water-swellable polymer or water-soluble polymer, and the second water-swellable water-insoluble polymer; and approximately 1-30% by weight of the hydrophilic polymer.
32. The composition according to claim 31, further characterized in that the complementary oligomer represents approximately 1-85% by weight of the hydrophilic polymer / complementary oligomer mixture. The composition according to claim 1, further characterized in that it comprises approximately 1-30% by weight of the first water-swellable polymer or water-soluble polymer, and the second water-swellable water-insoluble polymer; and approximately
0. 1-20% by weight of the hydrophilic polymer.
34. - The composition according to claim 33, further characterized in that the complementary oligomer represents approximately 1-85% by weight of the hydrophilic polymer / complementary oligomer mixture.
The composition according to claim 1, further characterized in that it comprises approximately 1-20% by weight of the first water-swellable polymer or water-soluble polymer, and the second water-swellable water-insoluble polymer; and about 20-80% by weight of the hydrophilic polymer.
36. The composition according to claim 35, further characterized in that the complementary oligomer represents approximately 10-80% by weight of the hydrophilic polymer / complementary oligomer mixture.
37.- The composition according to claim 1, further characterized in that it comprises approximately 20-80% by weight of the first water-swellable polymer or water-soluble polymer, and the second water-swellable water-insoluble polymer; and approximately 1-20% by weight of the hydrophilic polymer.
38.- The composition according to claim 37, further characterized in that the complementary oligomer represents approximately 10-80% by weight of the hydrophilic polymer / complementary oligomer mixture.
39.- A method for whitening teeth, comprising: applying the composition according to claim 1, to teeth that need bleaching; and remove the composition when the desired degree of whiteness has been achieved.
40. The method according to claim 39, further characterized in that the desired degree of whiteness is achieved after a predetermined period.
41. The method according to claim 40, further characterized in that the predetermined period is from about 10 minutes to about 24 hours.
42. The method according to claim 41, further characterized in that the predetermined period is from about 10 minutes to about 8 hours.
43.- The method according to claim 42, further characterized in that the predetermined period is from about 30 minutes to 1 hour.
44. The method according to claim 39, further characterized in that the composition can be used for an extended period.
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