Mucoadhesive compositions comprising divalent cation donors and methods of curing same

Abstract

The present invention provides a mucoadhesive composition comprising: (a) a lower alkyl vinyl ether-maleic acid copolymer in the form of a non-neutralized diacid; (b) a sodium carboxymethyl cellulose (Na-CMC) polymer; (c) a cross-linked polyvinylpyrrolidone (PVPP) polymer that is insoluble in water and swellable in water; (d) at least one divalent (M + +) cation donor; (e) at least one neutralizing agent; and (f) at least one oral care ingredient. In addition, the invention also provides a method for curing the mucoadhesive composition in situ at the application site.

Description

Technical Field

[0001] The processes, steps, methods, products, results, and / or concepts disclosed herein (collectively referred to as "this application, this disclosure, or the invention") generally refer to mucosal adhesive compositions having a divalent cation donor and a neutralizing agent. Background Technology

[0002] This invention relates to a mucosal adhesive composition having a divalent cation donor and a neutralizing agent.

[0003] Mucosal adhesive compositions, including denture fixatives or denture adhesive formulations, are typically provided in the form of creams, powders, or extruded dry sheets / films to provide users of partial or complete dentures with secure retention of their prostheses in the oral cavity, or to deliver therapeutic active ingredients to target areas within the oral cavity through topical application. Typically, mucosal adhesive compositions, including denture adhesive creams, consist of a water-soluble or water-swellable adhesive polymer suspended in an oral-acceptable carrier matrix, which is usually composed of varying proportions of long-chain hydrocarbons or long-chain fatty acids (such as mineral oil, vegetable oil, petrolatum, etc.). During use, the adhesive component in the mucosal adhesive composition (especially denture adhesive creams) is activated upon contact with saliva, causing the denture adhesive formulation applied between the gingiva and the denture to hydrate, swell, and subsequently form an adhesive and cohesive retention. The duration and strength of the adhesive retention provided by the denture adhesive formulation are key quantitative performance parameters of the denture adhesive. Other semi-quantitative or qualitative parameters used to define the overall performance characteristics of denture adhesive formulations may include: the film thickness and cushioning effect of the denture adhesive formulation between the gingiva and the denture; preventing food particles from entering the gap space between the gingiva and the denture by providing excellent gap sealing; and preventing the denture adhesive material from leaking between the gingiva and the denture due to exudation during use. Since common mucosal adhesive compositions, including denture adhesive creams, are essentially suspensions or dispersions of solid active ingredients in a semi-solid or liquid matrix composed of various oils, the loss of shelf-life stability of the formulation due to dehydration shrinkage of the carrier matrix and its separation from the solid active ingredient can also negatively impact adhesive performance.

[0004] Therefore, an ideal mucosal adhesive composition (especially denture fixation cream) should have suitable shelf-life stability over a sustained period of time; provide sufficiently high immediate dry and wet tack and long-lasting adhesion retention during use; provide adequate cushioning between the gingiva and denture to ensure comfortable use; seal the gap between the denture and gingiva to prevent food particles from entering the gap; reduce oral discomfort caused by partial hydration of the denture adhesive seeping between the gingiva and denture; and be easy to clean after use.

[0005] U.S. Patent Publication No. 20220401395A1 (owned by ISP Investments LLC) describes a mucosal adhesive composition comprising a denture adhesive composition, comprising, based on the total weight of the composition: (i) 10 wt% to about 75 wt% of a maleic acid or anhydride copolymer; (ii) 10 wt% to about 50 wt% of a cellulose ether; (iii) 0.1 wt% to 10 wt% of a water-swellable but water-insoluble crosslinked polyvinylpyrrolidone; and (iv) 30 wt% to 70 wt% of an orally acceptable carrier. Methods of use and processes for its preparation are also disclosed.

[0006] Japanese Patent No. 06908965B2 (owned by Kobayashi Pharmaceutical Co., Ltd.) discloses a denture stabilizer comprising the following components (A) and (B): (A) at least one adhesive component selected from lower alkyl vinyl ether / maleic anhydride copolymers, derivatives thereof, and salts thereof, and (B) a hydrogen phosphate.

[0007] PCT Publication No. WO199210988A1 (owned by Richardson-Vicks, Inc.) discloses an adhesive and stabilizer composition comprising a lower alkyl vinyl ether-maleic acid copolymer and its salt, said copolymer having a specific viscosity greater than 1.2, said specific viscosity being measured in methyl ethyl ketone at 25°C, and said copolymer having a bulk density of about 0.3 to about 1.2 g / cm³ and a specific surface area of ​​about 0.5 to about 2.5 m² / g.

[0008] In view of the above, there is still a need for an ideal mucosal adhesive composition with the following advantages: the main adhesive polymer has controllable solubility and activation, provides extended duration of adhesive / adhesive fixation, and controllable exudation.

[0009] Surprisingly, it was discovered that through divalent (M) ++ In-situ hydration of cation donors generates divalent cations (M). ++ This allows the lower-grade alkyl vinyl ether-maleic acid copolymer to crosslink with sodium carboxymethyl cellulose and form a stronger interpenetrating network, resulting in improved adhesion and / or tackiness under significantly lower-grade alkyl vinyl ether-maleic acid copolymer conditions; and also provides better exudation control by utilizing water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP). Summary of the Invention

[0010] One aspect of this application is to provide an adhesive film composition comprising: (a) about 2% to about 60% by weight of a lower alkyl vinyl ether-maleic acid copolymer in the form of a non-neutralized diacid; (b) about 5% to about 60% by weight of a sodium carboxymethyl cellulose (Na-CMC) polymer; (c) about 0.5% to about 10% by weight of a water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP) polymer; and (d) about 0.5% to about 25% by weight of at least one divalent (M... ++ (e) a cation donor; (f) at least one neutralizing agent in amounts from about 0.5% to about 25% by weight; and (c) at least one orally acceptable carrier or oral care ingredient or both in amounts from about 0.001% to about 90% by weight.

[0011] Another aspect of this application is a method for providing an in-situ curing adhesive composition for a mucosa, the adhesive composition comprising (a) about 2% to about 60% by weight of a non-neutralized diacid form of a lower alkyl vinyl ether-maleic acid copolymer; (b) about 5% to about 60% by weight of a sodium carboxymethyl cellulose (Na-CMC) polymer; (c) about 0.5% to about 10% by weight of a water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP) polymer; and (d) about 0.5% to about 25% by weight of at least one divalent (M... ++ (e) a cation donor; (f) at least one neutralizing agent of about 0.5% to about 25% by weight; and (c) at least one orally acceptable carrier or oral care ingredient, or both, of about 0.001% to about 90% by weight; the method comprising the steps of: (a) providing about 0.01% to about 99.9% by weight of a mucosal adhesive composition at the application site; (b) in the presence of a hydrating agent or the introduction of a hydrating agent, via a divalent (M ++ In situ release of divalent (M) cation donors during hydration. ++ (c) a divalent cation mediates the crosslinking of a lower alkyl vinyl ether-maleic acid copolymer; (d) an interpenetrating polymer network (IPN) of a lower alkyl vinyl ether-maleic acid copolymer and carboxymethyl cellulose; and (e) an in-situ activated and cured mucosal adhesive composition. Detailed Implementation

[0012] Before explaining in detail at least one aspect of the inventive concept disclosed and / or claimed, it should be understood that the inventive concept disclosed and / or claimed is not limited to the details of the construction and arrangement of the components, steps, or methods shown in the following description or drawings. The inventive concept disclosed and / or claimed can be implemented or performed in other aspects or in various ways. It should also be understood that the wording and terminology used herein are for descriptive purposes only and should not be considered as limiting the invention.

[0013] Unless otherwise stated, the following terms as used in this disclosure shall have the following meanings.

[0014] Unless otherwise defined herein, technical terms relating to this disclosure and / or the claimed inventive concepts shall have the meanings commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include plural terms and plural terms shall include singular terms.

[0015] The singular forms “a,” “an,” and “the” include the plural forms unless the context in which the reference is made explicitly specifies or clearly implies the opposite meaning. The terms “comprising” and “including” include more restrictive statements such as “consisting essentially of” and “composed of.”

[0016] For the purposes of the following detailed description, except in any operational instance or otherwise illustrated, numerical values ​​representing quantities of ingredients as used in the specification and claims should be understood to be modified by the term "about" in all cases. The numerical parameters set forth in the specification and appended claims are approximate values ​​and may vary depending on the desired properties obtained in practicing the invention.

[0017] Unless otherwise stated, all percentages, parts, proportions, and ratios herein are based on the total weight of the composition. All weights of the listed ingredients are based on activity levels and therefore, unless otherwise stated, do not include solvents or byproducts that may be present in commercially available materials.

[0018] All publications, articles, papers, patents, patent disclosures and other references cited in this article are incorporated herein in their entirety for all purposes and to the extent consistent with the disclosure herein.

[0019] The term "at least one / type" will be understood to include one / type as well as any quantity greater than one / type, including but not limited to 1, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. Depending on the modified term, the term "at least one / type" can be extended to 100 or 1000 or more.

[0020] Furthermore, the 100 / 1000 ratio should not be considered a limitation, as lower or higher limits may also produce satisfactory results.

[0021] As used herein, the terms “comprising” (and any form of “comprising” such as “comprise”, “comprises”), “having” (and any form of “having” such as “have” and “has”), “including” (and any form of “including” such as “includes” and “include)”), or “containing” (and any form of “containing” such as “contains” and “contain)”) are inclusive or open-ended and do not exclude other unlisted elements or methodological steps.

[0022] The term "independently selected" means that when a group appears more than once in a structure, that group can be selected independently each time it appears.

[0023] The term "polymer" refers to a compound comprising repeating structural units (monomers) linked by covalent chemical bonds. Polymers can be further derivatized, crosslinked, grafted, or end-capped. Non-limiting examples of polymers include copolymers, terpolymers, tetrpolymers, quaternary polymers, and homologues. The term "copolymer" refers to a polymer obtained by polymerizing essentially two or more monomers of different types.

[0024] The terms “denture fixation agent” or “mucosal adhesive” or “denture adhesive” refer to an adhesive that is pasted or adhered to the skin or mucus or mucosal cells or the surface of teeth.

[0025] As used herein, “denture” includes partial or full maxillary or mandibular dentures, or all of the above types. Ideally, the composition should serve as an effective means of isolating, cushioning, and securely positioning the denture. The composition should retain the characteristics and properties of its powder and cream forms during storage under various climatic conditions (such as temperature and humidity); be readily and easily applied to denture surfaces; be non-irritating and non-discomforting to the user; be safe and non-toxic; have no unpleasant odor or color; have no unacceptable taste; should not promote the growth of harmful tissues or microorganisms commonly found in the oral cavity; and should not promote the putrefaction or foul decomposition of food or secretions retained under or near the denture.

[0026] As used herein, “lower alkyl vinyl ether-maleic acid copolymer in diacid form” refers to a predetermined weight-average molecular weight of about 500,000 to 3,000,000 suitable for denture adhesives, wherein the lower alkyl vinyl ether-maleic acid copolymer in diacid form is prepared by the following steps: copolymerizing about 50 molar percentage of maleic anhydride and about 50 molar percentage of C1-C4 alkyl vinyl ether in the presence of a free radical initiator at a temperature of about 50°C to 150°C using a solvent or solvent-free process to obtain a uniform fine powder with substantially no residual maleic anhydride.

[0027] Alkyl vinyl ether maleic anhydride copolymers are obtained by copolymerizing alkyl vinyl ether monomers (such as methyl vinyl ether, ethyl vinyl ether, divinyl ether, propyl vinyl ether, and isobutyl vinyl ether) with maleic anhydride to form the corresponding alkyl vinyl ether-maleic anhydride copolymer, which is readily hydrolyzed to an acid copolymer. The anhydride and acid form are also available from commercial suppliers. For example, Ashland Inc. offers both the polymer in a free acid form and the corresponding anhydride form under its trademark "GANTREZ," namely "GANTREZ S Series."

[0028] As used herein, “cellulose ether” refers to a cellulose derivative obtained by etherifying the hydroxyl groups of cellulose using an etherifying agent. Available cellulose ethers include methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydrophobically modified hydroxyalkylcellulose, sodium carboxymethylcellulose, and mixtures thereof.

[0029] As used herein, the term "monovalent cation" refers to a cation having a single valence (M). + Accordingly, the term "divalent cation" refers to a cation having two valences (M). ++ The monovalent cation is selected from sodium, potassium, lithium, and combinations thereof. The monovalent cation is sodium. The divalent cation is selected from calcium, magnesium, strontium, iron, zinc, tin, copper, and combinations thereof. More preferably, the divalent cation is calcium, magnesium, zinc, and combinations thereof.

[0030] As used herein, “crosslinked or crosslinked” means that the composition contains intramolecular and / or intermolecular connections, whether generated by covalent or non-covalent bonding. “Non-covalent” bonding includes hydrogen bonding and electrostatic (ionic) bonding.

[0031] As used herein, the term “interpenetrating polymer network” or “IPN” refers to a blend of two or more polymers in a network form, wherein at least one polymer is synthesized and / or crosslinked in the close presence of the other polymers. IPNs can be distinguished from polymer blends, blocks, or grafts in two ways: (1) IPNs swell in a solvent but do not dissolve; and (2) creep and flow are suppressed.

[0032] As used in this article, the term "in situ" refers to a specific oral location on the skin or mucous membrane, mucous membrane cells, or denture surface.

[0033] As used herein, the term "functionalization" in relation to the carboxymethyl cellulose of this application refers to the presence of monovalent and one or more divalent cations on the carboxymethyl cellulose molecule. Various monovalent and divalent cations can be introduced into carboxymethyl cellulose by one or more functionalization reactions known to those skilled in the art. Non-limiting examples of functionalization reactions include ion exchange processes, which include (i) at least one monovalent (M... + (ii) Carboxymethyl cellulose salt and one or more divalent (M) ++ The reaction of metal salts; wherein the divalent (M) ++ Salt selected from M ++ Chloride or M ++ Sulfate or M ++ Carbonate, wherein M in the CMC polymer + With M ++ The weight ratio is approximately 1:70 to approximately 70:1.

[0034] As used in this article, including examples, the following abbreviations specifically refer to the following: (i) PVP: Polyvinylpyrrolidone; (ii) MVE: Methyl vinyl ether; (iii) MA: maleic anhydride / maleic acid; (iv) Na-CMC: Sodium carboxymethyl cellulose; (v) wt. %: weight percentage; (vi) FlexiThix: Slightly to moderately cross-linked polyvinylpyrrolidone; (vii) Polyplasdone XL-10: Self-crosslinking polyvinylpyrrolidone; (viii) PVP K-90: ​​Polyvinylpyrrolidone powder with an average molecular weight of 1,300,000 Daltons; (ix) Aqualon CMC 7H3SXF: Sodium carboxymethyl cellulose; (x) PVP K-15: Polyvinylpyrrolidone powder with an average molecular weight of 8,000 Daltons, and (xi) Other cellulose ethers such as HEC, HPC, EC, and cellulose ethers modified with divalent cations.

[0035] In a non-limiting embodiment, this application provides an adhesive film composition comprising: (a) about 2% to about 60% by weight of a lower alkyl vinyl ether-maleic acid copolymer in the form of a non-neutralized diacid; (b) about 5% to about 60% by weight of a sodium carboxymethyl cellulose (Na-CMC) polymer; (c) about 0.5% to about 10% by weight of a water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP) polymer; and (d) about 0.5% to about 25% by weight of at least one divalent (M... ++ (e) a cation donor; (f) at least one neutralizing agent in amounts from about 0.5% to about 25% by weight; and (c) at least one orally acceptable carrier or oral care ingredient in amounts from about 0.001% to about 90% by weight.

[0036] In another non-limiting embodiment, this application provides an adhesive composition for mucous membranes, wherein the maleic acid copolymer comprises maleic acid and lower alkyl groups (C3-C4). 12 Vinyl ether, having a predetermined weight-average molecular weight of about 500,000 to 3,000,000 suitable for denture adhesives, is prepared by the following steps: in a solvent- or solvent-free process, in the presence of a free radical initiator, about 50 mol% of maleic anhydride and about 50 mol% of C1-C 12 Alkyl vinyl ethers are copolymerized at temperatures ranging from about 50°C to 150°C to obtain a uniform fine powder with virtually no residual maleic anhydride.

[0037] In another non-limiting embodiment, the lower alkyl group of the vinyl ether-maleic acid copolymer has 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 3 to 6 carbon atoms.

[0038] In another non-limiting embodiment, the methyl vinyl ether-maleic acid (MVE-MA) copolymer has a number-average molecular weight of about 50,000 to about 3,000,000 Daltons.

[0039] In another non-limiting embodiment, the number average molecular weight (in Daltons) of the lower alkyl vinyl ether-maleic acid copolymer is about 50,000 to about 100,000, about 300,000 to about 500,000, about 500,000 to about 600,000, about 600,000 to about 900,000, about 900,000 to about 1,200,000, about 1,200,000 to about 1,500,000, about 1,500,000 to about 1,800,000, about 1,800,000 to about 2,100,000, about 2,100,000 to about 2,500,000, about 2,500,000 to about 2,800,000, or about 2,800,000 to about 3,000,000.

[0040] In another non-limiting embodiment, the salt of the alkyl vinyl ether-maleic acid copolymer has a specific viscosity of about 2.5 to about 5.0 as measured at 25°C in a 1% by weight / volume methyl ethyl ketone (MEK) solution.

[0041] In another non-limiting embodiment, the lower alkyl vinyl ether-maleic acid copolymer has a specific viscosity of about 2.5 to about 3.0, about 3.0 to about 3.5, about 3.5 to about 4.0, about 4.0 to about 4.5, and about 4.5 to about 5.0 when measured at 25°C in a 1 wt / vol% methyl ethyl ketone (MEK) solution.

[0042] In another non-limiting embodiment, the content of the lower alkyl vinyl ether-maleic acid copolymer is from about 5% to about 50% by weight of the total composition. Further, the content of the lower alkyl group in the vinyl ether-maleic acid copolymer is from about 5% to 10% by weight, from about 10% to about 15% by weight, from about 15% to about 20% by weight, from about 20% to 25% by weight, from about 25% to about 30% by weight, from about 30% to about 35% by weight, from about 35% to about 40% by weight, from about 40% to about 45% by weight, or from about 45% to about 50% by weight.

[0043] In another non-limiting embodiment, the mucosal adhesive composition comprises a sodium salt of carboxymethyl cellulose (Na-CMC). Cellulose ethers available herein include sodium carboxymethyl cellulose from the 7H series available from Aqualon, which, according to its datasheet, has a typical molecular weight of approximately 700,000 Daltons. Other examples of available carboxymethyl cellulose include 7H3SX8F and 7H3SXF, both available from Aqualon / Hercules, and CEKOL30,000P, available from CP Kelco / Noviant / Huber. In some embodiments, the sodium carboxymethyl cellulose used in the composition is 7H3SXF.

[0044] In another non-limiting embodiment, this application discloses that the sodium carboxymethyl cellulose has a molecular weight between medium and high. In some embodiments, the medium to high weight-average molecular weight ranges from about 2,000 to about 1,500,000 Daltons. In some embodiments, the medium molecular weight range is about 10,000 to about 15,000 Daltons, or about 15,000 to about 20,000 Daltons, or about 20,000 to about 300,000, or about 30,000 to about 40,000 Daltons, or about 40,000 to about 50,000 Daltons, or about 50,000 to about 60,000 Daltons, or about 60,000 to about 70,000 Daltons, or about 70,000 to about 80,000 Daltons. In some embodiments, the high molecular weight range is about 80,000 to about 90,000 Daltons, or about 90,000 to about 100,000 Daltons, or about 100,000 to about 200,000 Daltons, or about 200,000 to about 300,000 Daltons, or about 300,000 to about 400,000 Daltons, or about 400,000 to about 500,000 Daltons. Daltons, or about 500,000 to about 600,000 Daltons, or about 600,000 to about 700,000 Daltons, or about 700,000 to about 800,000 Daltons, or about 800,000 to about 900,000 Daltons, or about 900,000 to about 1,000,000 Daltons, or about 1,000,000 to about 1,100,000 Daltons.

[0045] In another non-limiting embodiment, the sodium carboxymethyl cellulose (Na-CMC) content is from about 5% to about 60% by weight of the total composition. Further, the sodium carboxymethyl cellulose (Na-CMC) content is from about 5% to about 10% by weight, from about 10% to about 15% by weight, from about 15% to about 20% by weight, from about 20% to about 25% by weight, from about 25% to about 30% by weight, from about 30% to about 35% by weight, from about 35% to about 40% by weight, from about 40% to about 45% by weight, from about 45% to about 50% by weight, from about 50% to about 55% by weight, or from about 55% to about 60% by weight of the total composition.

[0046] In another non-limiting embodiment, this application provides a strongly swollen, moderately crosslinked PVP (polyvinylpyrrolidone) polymer, commercially available from Ashland Inc. under the trademarks FlexiThix™ or Polyplasdone™, which can be directly obtained in fine powder form by precipitation polymerization of vinylpyrrolidone in an organic solvent in the presence of a predetermined amount of a multifunctional crosslinking agent and a free radical initiator. The crosslinked PVP has a Brookfield viscosity of at least about 500 to about 50,000 centipoise (cps) in a 4% aqueous solution. Preferred viscosity ranges for the crosslinked PVP described in this application may be about 500 to about 50,000 centipoise, or about 800 to about 20,000 centipoise, or about 1,000 to about 10,000 centipoise. Brookfield viscosity can be determined at 2.5, 5, 10, 12, 20, 30, or 50 RPM and 25°C.

[0047] The crosslinked PVP polymers available in practice under this application can be prepared according to U.S. Patent Nos. 5,073,614 and 5,130,388 to ISP Investments Inc. The teachings of these references are advantageously adopted for the purposes of this application. Furthermore, the entire contents of these references are incorporated herein by reference.

[0048] One element of the thickening additive composition according to this application is a thickener comprising a strongly swollen, mildly to moderately crosslinked polyvinylpyrrolidone as described in commonly owned U.S. Patent Nos. 5,312,619 and 5,139,770, the contents of which are hereby incorporated by reference in their entirety. Unless otherwise stated, the term “strongly swollen, mildly to moderately crosslinked PVP” specifically refers to a polymer consisting primarily of mildly to moderately crosslinked poly(N-vinyl-2-pyrrolidone) having at least one of the following non-limiting characteristics: (1) a water swelling parameter defined by its gel volume of about 15 mL / g to about 300 mL / g, more specifically about 15 mL / g to about 250 mL / g, and in other cases about 15 mL / g to about 150 mL / g; or (2) a Brookfield viscosity (measured at 25°C in a water-containing liquid carrier with 5% crosslinked PVP) of at least 2,000 cP, more specifically preferably at least about 5,000 cP, and in some cases at least about 10,000 cP. Reference to these parameter ranges is provided in U.S. Patent No. 5,073,614 (incorporated herein by reference) and Shih, JS et al. (1995). The method for synthesizing the crosslinked PVP described herein is disclosed in numerous references, including U.S. Patents 5,073,614, 5,654,385, and 6,177,068, the entire contents of which are hereby incorporated by reference. Polymer scientists in the art will understand that various synthesis methods are feasible provided the prepared polymer meets at least one of the aforementioned defined parameters.

[0049] Crosslinked polyvinylpyrrolidone is a commercially available product, such as BASF's Kollidon® CL type or Ashland Inc's Polyplasdone® XL and Flexithix™ type PVP. In another non-limiting embodiment, this application provides a swellable crosslinked PVP polymer that can be directly prepared as a white fine powder by precipitation polymerization of vinylpyrrolidone in an organic solvent in the presence of a predetermined amount of a crosslinking agent and a free radical polymerization initiator, wherein the organic solvent is preferably an aliphatic hydrocarbon, such as C3-C4. 10 Saturated branched or straight-chain cyclic or acyclic aliphatic hydrocarbons, with cyclohexane or heptane or mixtures thereof being the most preferred.

[0050] In various embodiments of this application, crosslinked polymers of vinylpyrrolidone (including copolymers of vinylpyrrolidone with other monomeric materials) that remain in porous particle or bead form even when wetted and swollen are produced by a process in which the monomeric material is polymerized with a controlled amount of crosslinking agent in an aqueous electrolyte solution. An insoluble polymer is formed, and excess monomer is kept in suspension by mechanical stirring.

[0051] In various embodiments of the invention, the crosslinked vinylpyrrolidone polymer provides a degree of rigidity to the hydrated denture adhesive during use, preventing the hydrogel from structurally disintegrating and thus causing the denture adhesive to leak between the gums and the denture due to exudation.

[0052] In another non-limiting embodiment, the crosslinked polyvinylpyrrolidone (PVPP) provided in this application ranges from about 0.5% by weight to about 10% by weight of the total composition. Accordingly, the crosslinked polyvinylpyrrolidone (PVPP) ranges from about 0.5% by weight to about 1% by weight, about 1.0% by weight to about 2% by weight, about 2% by weight to about 4% by weight, about 4% by weight to about 6% by weight, about 6% by weight to about 8% by weight, or about 8% by weight to about 10% by weight of the total composition.

[0053] In another non-limiting embodiment, this application provides a bivalent (M) selected from the following ++ Cation donor: Calcium (Ca ++ ), Strontium (Sr) ++ ), Zinc (Zn) ++ ), magnesium (Mg) ++ ), iron (Fe) ++ ), Vanadium (V) ++ ), chromium (Cr) ++ ), manganese (Mn) ++ ), nickel (Ni ++ ), copper (Cu) ++ ), Yttrium (Y ++ ) and its mixtures.

[0054] In another non-limiting embodiment, the divalent (M) ++ The cation donor is a salt selected from the following: acetate, carboxylate, gluconate, halide, hydroxide, carbonate, lactate, oxide, phosphate, sulfate, and combinations thereof of divalent cations.

[0055] In another non-limiting embodiment, the divalent (M) ++The cation salt is selected from calcium acetate, calcium carbonate, calcium chloride, calcium 2-ethylbutyrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium oxide, calcium propionate, calcium sulfate, calcium magnesium acetate, magnesium acetate, magnesium chloride, magnesium propionate, zinc chloride, zinc acetate, and combinations thereof.

[0056] In another non-limiting embodiment, the divalent (M) ++ The content of the cation donor is from about 1% to about 20% by weight of the total composition. Further, the divalent (M... ++ The content of the cation donor is from about 1% to about 5% by weight, from about 5% to about 10% by weight, from about 10% to about 15% by weight, or from about 15% to about 20% by weight of the total composition.

[0057] In another non-limiting embodiment, the neutralizing agent is a salt selected from the following: monovalent (M... + ) cations or divalent (M) ++ Hydroxides of cations, monovalent (M) + ) cations or divalent (M) ++ Phosphates of cations, pyrophosphates of monovalent or divalent cations, hydrogen phosphates of monovalent or divalent cations, carbonates or bicarbonates of monovalent or divalent cations, tripolyphosphates or metaphosphates of monovalent or divalent cations, hydroxides of monovalent or divalent cations, and combinations thereof.

[0058] In various embodiments of the present invention, the neutralizing agent is selected from monovalent (M) + ) cations or divalent (M) ++ Phosphates of cations, pyrophosphates of monovalent or divalent cations, hydrogen phosphates of monovalent or divalent cations, carbonates or bicarbonates of monovalent or divalent cations, orthometaphosphates of monovalent or divalent cations, and combinations thereof.

[0059] Accordingly, the neutralizing agent is selected from sodium hydroxide, sodium orthometaphosphate, disodium hydrogen phosphate, trisodium phosphate, sodium tripolyphosphate, tetrasodium pyrophosphate, sodium hexametaphosphate, potassium hydroxide, dipotassium hydrogen phosphate, and mixtures thereof.

[0060] In another non-limiting embodiment, the neutralizing agent is present in an amount of about 0.5% by weight to about 20% by weight of the total composition. Further, the neutralizing agent is present in an amount of about 0.5% by weight to about 5% by weight, about 5% by weight to about 10% by weight, about 10% by weight to about 15% by weight, or about 15% by weight to about 20% by weight of the total composition.

[0061] In another non-limiting embodiment, the application further comprises about 0.5% to about 60% by weight of at least one additional cellulose polymer selected from lower alkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, divalent cation-modified carboxymethyl cellulose, and mixtures thereof.

[0062] In another non-limiting embodiment, the application further comprises at least one additional cellulose polymer in amounts of about 0.5 wt% to about 5 wt%, about 5 wt% to about 10 wt%, about 10 wt% to about 15 wt%, about 15 wt% to about 20 wt%, about 20 wt% to about 25 wt%, about 25 wt% to about 30 wt%, about 30 wt% to about 35 wt%, about 35 wt% to about 40 wt%, about 40 wt% to about 45 wt%, about 45 wt% to about 50 wt%, about 50 wt% to about 55 wt%, and about 55 wt% to about 60 wt%.

[0063] Accordingly, the additional cellulose polymer has a weight-average molecular weight range of about 2,000 to about 1,500,000 Daltons. In some embodiments, the intermediate molecular weight range is about 10,000 to about 15,000 Daltons, or about 15,000 to about 20,000 Daltons, or about 20,000 to about 300,000 Daltons, or about 30,000 to about 40,000 Daltons, or about 40,000 to about 50,000 Daltons, or about 50,000 to about 60,000 Daltons, or about 60,000 to about 70,000 Daltons, or about 70,000 to about 80,000 Daltons. In some embodiments, the high molecular weight range is about 80,000 to about 90,000 Daltons, or about 90,000 to about 100,000 Daltons, or about 100,000 to about 200,000 Daltons, or about 200,000 to about 300,000 Daltons, or about 300,000 to about 400,000 Daltons, or about 400,000 to about 500,000 Daltons, or about 500,000 to about 600,000 Daltons, or about 600,000 to about 700,000 Daltons, or about 700,000 to about 800,000 Daltons, or about 800,000 to about 900,000 Daltons, or about 900,000 to about 1,000,000 Daltons, about 1,000,000 to about 1,100,000 Daltons, about 1,100,000 to about 1,200,000 Daltons, about 1,200,000 to about 1,300,000 Daltons, about 1,300,000 to about 1,400,000 Daltons, or about 1,400,000 to about 1,500,000 Daltons.

[0064] In another non-limiting embodiment, the additional cellulose polymer provided in this application is carboxymethyl cellulose (CMC) functionalized with at least one monovalent (M) + ) cations and at least one divalent (M ++ (i) cation; or (ii) at least one divalent cation functionalized. The additional cellulose polymer is selected from carboxymethyl cellulose (CMC): (i) sodium-calcium carboxymethyl cellulose (Na) + -Ca ++ -CMC), (ii) Sodium-magnesium carboxymethyl cellulose (Na + -Mg ++ -CMC), (iii) sodium carboxymethyl cellulose-zinc (Na + -Zn ++ (iv) Sodium carboxymethyl cellulose-calcium-zinc (Na)+ -Ca ++ -Zn ++ -CMC), (v) sodium carboxymethyl cellulose-calcium-magnesium (Na) + -Ca ++ -Mg ++ -CMC), (vi) sodium carboxymethyl cellulose-magnesium-zinc (Na + -Mg ++ -Zn ++ -CMC), (vii) sodium carboxymethyl cellulose-tin (Na + -Sn ++ -CMC), (viii) Sodium carboxymethyl cellulose-calcium-tin (Na + -Ca ++ -Sn ++ -CMC), (ix) sodium carboxymethyl cellulose-magnesium-tin (Na + -Mg ++ -Sn ++ -CMC), or (x) sodium carboxymethyl cellulose-zinc-tin (Na + -Zn ++ -Sn ++ -CMC), (xi) carboxymethyl cellulose calcium (Ca ++ -CMC), (xii) carboxymethyl cellulose magnesium (Mg ++ -CMC), (xiii) carboxymethyl cellulose zinc (Zn ++ -CMC) or (xiv) carboxymethyl cellulose tin (Sn) ++ -CMC).

[0065] In another non-limiting embodiment, the mucosal adhesive composition provides one or more oral care acceptable ingredients selected from adhesion promoters, additional modified cellulose ethers, anti-caking agents, antifungal agents, antimicrobial agents, antigingivitis agents, anesthetics, antioxidants, antibiotics, anti-inflammatory agents, adhesives, buffers, pigments, cooling agents, dentin desensitizers, dispersants, enzymes, lubricants, flavorings, fillers, fragrances, gelling agents, humectants, hydrophilic non-oil components, oil carriers, exudation control polymers, preservatives, pigments, plasticizers, analgesics, sweeteners, thickeners, viscosity modifiers, carriers, surfactants, stabilizers, sensory agents, and mixtures thereof.

[0066] In another embodiment, the content of the oral care acceptable ingredient is from about 0.001% by weight to about 90% by weight of the total composition. Further, the content of the oral care ingredient is from about 0.001% by weight to about 10% by weight, from about 10% by weight to about 20% by weight, from about 20% by weight to about 30% by weight, from about 30% by weight to about 40% by weight, from about 40% by weight to about 50% by weight, from about 50% by weight to about 60% by weight, from about 60% by weight to about 70% by weight, from about 70% by weight to about 80% by weight, and from about 80% by weight to about 90% by weight of the total composition.

[0067] Non-limiting examples of lubricants include hydrophobic oils or hydrophilic non-oil components.

[0068] Accordingly, the hydrophobic oil or hydrophilic non-oil component may be selected from liquid petrolatum, petrolatum, mineral oil, glycerin, natural and synthetic oils, fats, silicones and silicone derivatives, polyvinyl acetate, polyethylene glycol, propylene glycol, polypropylene glycol, poly(ethylene oxide-propylene oxide) copolymers, diethylene glycol, triethylene glycol, sorbitol, water, orally acceptable surfactants and mixtures thereof, natural and synthetic waxes such as animal waxes (e.g., beeswax, lanolin and shellac), hydrocarbons, hydrocarbon derivatives, vegetable oil waxes (e.g., carnauba wax, candela wax and bayberry wax), vegetable oils such as caprylic / capric triglycerides, vegetable oils (e.g., corn oil, sunflower oil, soybean oil, castor oil, palm oil, coconut oil, olive oil and rapeseed oil or mixtures thereof), and animal oils (e.g., fish oil and oleic acid), and mixtures thereof. Non-limiting examples of mineral oils include maleated avocado oils, maleated coconut oil, maleated corn oil, maleated cottonseed oil, maleated jojoba oils, maleated flaxseed oil, maleated nut oil, maleated olive oil, maleated palm oil, maleated raisin oil, maleated rapeseed oils, maleated safflower oil, maleated sesame oil, maleated soybean oil, maleated pumpkin seed oil, maleated sunflower seed oil, maleated almond oil, maleated canola oils, maleated flaxseedoils, maleated grapeseed oil, maleated palm oil, maleated palm kernel oil, maleated peanut oil, and maleated walnut oil.

[0069] In another non-limiting embodiment, the mineral oil is functionalized or unfunctionalized masoyedic soybean oil, wherein the functionalization includes hydrophilic or hydrophobic portions.

[0070] In some embodiments, the carrier based on the hydrophobic oil or hydrophilic non-oil component has a suitable content range relative to the total weight of the mucosal adhesive composition (including denture adhesive compositions) of about 10% to about 20% by weight, or about 20% to about 30% by weight, or about 30% to about 40% by weight, or about 40% to about 50% by weight, or about 50% to about 60% by weight, or about 60% to about 75% by weight.

[0071] Non-limiting examples of colorants are selected from talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminum silicate, silicon dioxide, titanium dioxide, zinc oxide, red iron oxide, brown iron oxide, yellow iron oxide, black iron oxide, ferric ammonium ferrocyanide, manganese violet, ultramarine, nylon powder, polyethylene powder, methacrylate powder, polystyrene powder, filament powder, crystalline cellulose, starch, titanate mica, iron oxide titanate mica, bismuth oxychloride, and mixtures thereof.

[0072] Non-limiting examples of flavoring agents include: (i) synthetic flavoring liquids and / or oils derived from the leaves, flowers, and fruits of plants, including vanillin, sage, marjoram, parsley oil, spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, clove oil, laurel oil, anise oil, and eucalyptus oil; (ii) artificial, natural, or synthetic fruit flavorings extracted from lemon, orange, banana, grape, lime, apricot, and grapefruit; (iii) fruit essential oils made from apple, strawberry, cherry, orange, and pineapple; (iv) flavorings derived from beans and nuts, including coffee, cocoa, cola, peanut, and almond; (v) flavorings adsorbed onto a hydrophilic matrix, such as “spray-dried” flavorings; and (vi) encapsulated flavorings.

[0073] The amount of flavoring agents used is generally related to preferences influenced by factors such as the type of flavoring and the desired flavor strength. The content of flavoring agents can be up to about 4% of the total composition weight, in one embodiment from about 0.05% to about 3.0%, and in another embodiment from about 0.8% to about 2.5%.

[0074] Non-limiting examples of antimicrobial compounds used in this composition may be selected from halogenated diphenyl ethers (such as triclosan), herbal extracts, and essential oils (such as rosemary extract, tea extract, magnolia extract, thymol, menthol, eucalyptol, geraniol, carvacrol, citral, pyraclostrobin, catechin, methyl salicylate, epigallocatechin gallate). Gallate, epigallocatechin, gallic acid, Miswak extract, sea buckthorn extract), biguanide disinfectants (such as chlorhexidine, alexidine, or octenidine), quaternary ammonium compounds (such as hexadecylpyridine chloride (CPC), benzalkonium chloride, tetradecylpyridine chloride (TPC), N-tetradecyl-4-ethylpyridine chloride (TDEPC)), phenolic disinfectants, hexetidine, octenidine, sanguisorbin, povidone-iodine, delmopinol, salifluor, metal ions (such as zinc salts, such as zinc chloride, zinc lactate, zinc sulfate, stannous salts, copper salts, iron salts), sanguisorbin, propolis, stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, and ammonium fluoride. The anti-inflammatory compounds of this application may be selected from, but are not limited to, the following: triamcinolone (trade name: Kenalog), fluocinonide (trade name: Vanos), dexamethasone (trade name: decadron), herpes, amphetaminex (aphthasol), ketorolac, flurbiprofen, ibuprofen, naproxen, indomethacin, aspirin, ketoprofen, piroxicam, and meclofenamic acid.

[0075] Non-limiting examples of analgesic compounds in this application may be selected from, but are not limited to, the group consisting of: benzocaine, lidocaine, procaine, prilocaine, mepivacaine, aspirin, ibuprofen, diclofenac, and methyl salicylate.

[0076] Non-limiting examples of antioxidant compounds in this application may be selected from, but are not limited to, the group consisting of: vitamin E, ascorbic acid, uric acid, carotenoids, vitamin A, flavonoids, polyphenols, herbal antioxidants, melatonin, aminoindole, lipoic acid, caffeic acid, β-carotene, ellagic acid, epicatechin, epicatechin gallate, ferulic acid, genistein, kojic acid, α-lipoic acid, lycopene, resveratrol, resorcinol, rosmarinic acid, silibinin, theaflavins, tocopherols, tocotrienols, trolox, and coenzyme Q-10.

[0077] Non-limiting examples of enzymes in this application may be selected from, but are not limited to, the following group: proteases: papain, bromelain, chymotrypsin, fig protease, and alkaline protease; glycoases: glucosylamylase, α-amylase, β-amylase, dextranase, and mutanas; lipases: plant lipase, gastric lipase, and pancreatic lipase; and glucosylamylase, derived from Aspergillus niger (… Aspergillus niger ) saccharifying glucose amylase.

[0078] Non-limiting examples of cooling agents in this application may be selected from, but are not limited to, the following: menthol, menthyl lactate, menthyl succinate, menthol ethylene glycol carbonate, menthol propylene glycol carbonate, menthone glycerol ketal, 3-(l-menthoxy)propane-1,2-diol, (-)-isopulegol, WS-31 [N-ethyl-p-menthane-3-carboxamido], WS-23 (2-isopropyl-N-2,3-trimethylbutyramide) and WS-5 [ethyl 3p-menthane-3-carboxamido)acetate].

[0079] The cooling agent of this application may be selected from, but is not limited to, the following group: acesulfame K, aspartame, neotame, saccharin, sucralose, stevia, advantame, cyclamate, sorbitol, xylitol and erythritol.

[0080] In some embodiments, based on the total weight of the mucosal adhesive composition, including the denture adhesive and denture fixation composition, the suitable content range of the antibacterial agent, anti-inflammatory agent, analgesic agent, antioxidant, enzyme, flavoring, cooling agent and sweetener is from about 0.01% by weight to about 0.1% by weight, or from about 0.1% by weight to about 1% by weight, or from about 1% by weight to about 10% by weight, or from about 10% by weight to about 20% by weight.

[0081] According to another embodiment of this application, it is anticipated that at least one excipient will be introduced. For the purposes of this application, suitable excipients are selected from preservatives, flavoring agents, coloring agents, sweeteners, plasticizers, binders, thickeners, carriers, colorants, flavorings, fragrances, sensates, and mixtures thereof.

[0082] In another non-limiting embodiment, this application discloses a method for preparing a mucosal adhesive composition and the use of such formulations for the sustained release of an active ingredient selected from, but not limited to, the group consisting of: antibacterial agents, anti-inflammatory agents, analgesics, antioxidants, enzymes, flavorings, cooling agents, and sweeteners.

[0083] In one embodiment, the mucosal adhesive composition is in the form of a dental cleaner, denture cleaner, chewing gum, lozenges, mouthwash, dental appliances, tooth powder, topical oral gel, denture product, soluble film, strip, oral tablet, sheet, oral gel in the form of chewing gum, oral ointment, buccal composition, sublingual composition, palatal composition, and denture adhesive composition.

[0084] In one embodiment, it is contemplated that materials suitable for use in mucosal adhesive compositions (including denture adhesives) are used, specifically materials that are safe and palatable when used in hygienic compositions (e.g., pastes, creams, gels, thermoplastic solids, hydrogels, or combinations thereof) at relevant concentrations.

[0085] In another non-limiting embodiment, the pH value of this mucosal adhesive composition is from about 5 to about 8.

[0086] In another non-limiting embodiment, this application provides a method for in-situ curing a mucosal adhesive composition comprising (a) about 2% to about 60% by weight of a non-neutralized diacid form of a lower alkyl vinyl ether-maleic acid copolymer; (b) about 5% to about 60% by weight of a sodium carboxymethyl cellulose (Na-CMC) polymer; (c) about 0.5% to about 10% by weight of a water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP) polymer; (d) about 0.5% to about 25% by weight of at least one divalent (M++) cationic donor; (e) about 0.5% to about 25% by weight of at least one neutralizing agent; and (f) about 0.001% to about 90% by weight of at least one orally acceptable carrier and / or oral care ingredient; the method comprising the steps of: (a) providing about 0.01% to about 99.9% by weight of the mucosal adhesive composition at the application site; (b) In the presence of or introduction of hydrating agents, through divalent (M ++ In situ release of divalent (M) cation donors during hydration.++ (c) a divalent cation mediates the crosslinking of a lower alkyl vinyl ether-maleic acid copolymer; (d) a lower alkyl vinyl ether-maleic acid copolymer interpenetrating polymer network (IPN) with carboxymethyl cellulose; and (e) an in-situ activated and cured mucosal adhesive composition.

[0087] Accordingly, the hydrating agent is water or saliva.

[0088] In another non-limiting embodiment, the mucosal adhesion composition is a denture fixation composition.

[0089] Furthermore, certain aspects of this application are described in detail through the following embodiments. The embodiments provided herein are for illustrative purposes only and are not intended to limit the scope of this application.

[0090] Example Example 1: Oil-based adhesive formulation A standard oil-based mucosal adhesive formulation was prepared in 200 g batches using a KitchenAid planetary mixer equipped with a CNC thermostatic heating jacket. The heating jacket was set to maintain a constant temperature of 194°F (90°C). The components required for preparing the mucosal adhesive cream were added according to Table 1. Vaseline and white mineral oil were added to the heating bowl of the KitchenAid mixer and mixed at low speed for 10 minutes until the Vaseline was completely melted and a homogeneous, clear liquid was formed. Sodium carboxymethyl cellulose was added to the KitchenAid and vigorously mixed with the oil for 30 minutes until uniformly dispersed. If applicable, other cellulose ethers were added to the mixing bowl of the KitchenAid and vigorously mixed for 10 minutes. Subsequently, poly(MVE / MA) diacid polymer powder was added to the KitchenAid and mixed at medium speed for 10 minutes to obtain a paste of uniform consistency. As shown in Table 1, neutralizing agents, divalent cation donors, and exudation control agents were added to the mixing bowl of the KitchenAid and then vigorously mixed for 30 minutes until a uniform paste was obtained. Add suitable pigments and other ingredients and mix until uniformly dispersed. Turn off the heat and allow the mucosal adhesive cream to cool to room temperature over a period of 2 hours with continuous stirring at medium speed. After cooling to room temperature, load 50g of the mucosal adhesive sample into a suitable dispensing tube and heat-seal. Store the remaining mucosal adhesive in a clear glass jar for storage stability studies.

[0091] Example 2: Test method for mucosal adhesives Adhesion forces and corresponding film thicknesses of the mucosal adhesives were recorded using a Stable Microsystems Texture Technologies Corp. TA.XT Plus texture analyzer equipped with a 50 kg load sensor and connected to a PC running Exponent software version 6.1.11.0. The texture analyzer was equipped with a custom-designed denture-shaped plexiglass probe-clamp assembly. Artificial saliva was infused between the walls of the plexiglass probe-clamp assembly via a peristaltic pump. Real-time time-lapse images of the mucosal adhesive creams used for adhesion performance evaluation on the texture analyzer were recorded using a Canon EOS 5d Mark IV Digital SLR camera.

[0092] Expel trapped air from the sample tube containing the mucosal adhesive cream, cap the tube, and squeeze it several times to homogenize the contents. Always discard the first 100 mg of material that comes out of the tube.

[0093] Three nearly identical strips of mucosal adhesive cream were weighed on an analytical balance and placed in the denture-shaped cavity of the bottom plexiglass clamp. The total mass of the mucosal adhesive cream applied to the bottom clamp in each test was 2.0 (+0.1) g. The bottom clamp was mounted on a texture analyzer, and the top probe was moved downward into the cavity of the bottom clamp to evenly spread the mucosal adhesive cream and fill the lower half of the cavity under a precise compression force of 4.5 kg. Artificial saliva infusion was initiated. Throughout the experiment, the mucosal adhesive cream remained in contact with and immersed in a thin layer of artificial saliva that was continuously renewed at a flow rate of 1 mL / min. Once the mucosal adhesive cream layer was completely covered with artificial saliva, a 7-hour test procedure was initiated. During the experiment, the adhesion force (in Newtons) at the moment of chewing and the thickness of the mucosal adhesive film (in millimeters) between the top and bottom probes were continuously measured. Four consecutive experimental runs were performed on each sample of the prepared mucosal adhesive formulation. For adhesion performance and thickness variation, the average curves of four runs for each sample were compared. The total adhesion force of each sample was obtained by calculating the area under the curve of the average curve of four consecutive runs for each sample (Examples 1, 4, 7-9, 14-18, 20, and 21), and the results are recorded in Table 1.

[0094] Table 1: Mucosal Adhesive Formulations and Total Adhesion The foregoing description fully discloses the present invention, including its preferred embodiments. Modifications and improvements to the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that those skilled in the art can fully implement the present invention based on the foregoing description. Embodiments of the present invention claiming exclusive rights or privileges are defined as follows.

Claims

1. A mucosal adhesive composition comprising: (a) About 2% by weight to about 60% by weight of lower alkyl vinyl ether-maleic acid copolymers in the form of unneutralized diacids; (b) Sodium carboxymethyl cellulose (Na-CMC) polymer, approximately 5% by weight to approximately 60% by weight; (c) About 0.5% by weight to about 10% by weight of a water-insoluble and water-swellable crosslinked polyvinylpyrrolidone (PVPP) polymer; (d) at least one divalent (M) compound, ranging from about 0.5% by weight to about 25% by weight. ++ ) cation donor; (e) at least one neutralizing agent comprising about 0.5% by weight to about 25% by weight; and (f) at least one oral care ingredient, from about 0.001% by weight to about 90% by weight.

2. The adhesive composition according to claim 1(a), wherein the lower alkyl group of the vinyl ether-maleic acid copolymer has about 1 to about 12 carbon atoms.

3. The adhesive composition according to claim 1(a), wherein the lower alkyl group of the vinyl ether-maleic acid copolymer has about 1 to about 8 carbon atoms.

4. The adhesive composition according to claim 3, wherein the lower alkyl vinyl ether-maleic acid copolymer is selected from methoxyethylene maleic acid copolymer, ethyl vinyl ether maleic acid copolymer, propyl vinyl ether maleic acid copolymer, isobutyl vinyl ether maleic acid copolymer, and mixtures thereof.

5. The mucosal adhesive composition according to claim 1(a), wherein the lower alkyl vinyl ether-maleic acid copolymer has an average molecular weight range of about 50,000 to about 3,000,000 Daltons.

6. The adhesive composition according to claim 1(a), wherein the lower alkyl vinyl ether-maleic acid copolymer has a specific viscosity of about 2.5 to about 5.0% as measured at 25°C in a 1% by weight / volume solution of methyl ethyl ketone (MEK).

7. The adhesive composition according to claim 1(a), wherein the content of the lower alkyl vinyl ether-maleic acid copolymer is from about 5% to about 50% by weight of the total composition.

8. The mucosal adhesive composition according to claim 1(b), wherein the number-average molecular weight of the sodium carboxymethyl cellulose is in the range of about 50,000 to about 1,000,000 Daltons.

9. The mucosal adhesive composition according to claim 1(b), wherein the sodium carboxymethyl cellulose content ranges from about 5% by weight to about 60% by weight of the total composition.

10. The mucosal adhesive composition according to claim 1(c), wherein the crosslinked polyvinylpyrrolidone (PVPP) has a gel volume of about 15 to about 300 ml / g.

11. The mucosal adhesive composition according to claim 1(c), wherein the crosslinked polyvinylpyrrolidone (PVPP) content ranges from about 0.5% by weight to about 10% by weight of the total composition.

12. The mucosal adhesive composition according to claim 1(d), wherein the divalent (M... ++ The cation donor is selected from: calcium (Ca) ++ Salt, Strontium (Sr) ++ Salt, Zinc (Zn) ++ ) salt, magnesium (Mg) ++ Salt, iron (Fe) ++ ) salt, vanadium (V ++ Salts, chromium (Cr) ++ Salt, manganese (Mn) ++ Salts, nickel (Ni) ++ Salt, copper (Cu) ++ Salt, Yttrium ++ Salt and its mixtures.

13. The mucosal adhesive composition according to claim 1(d), wherein the divalent (M... ++ The cation donor is selected from the following salts: acetate, carboxylate, gluconate, halide, hydroxide, lactate, oxide, phosphate, sulfate, and combinations thereof.

14. The mucosal adhesive composition of claim 13, wherein the divalent (M... ++ The cation salts are selected from calcium acetate, calcium carbonate, calcium chloride, calcium 2-ethylbutyrate, calcium gluconate, calcium hydroxide, calcium lactate, calcium oxide, calcium propionate, calcium sulfate, calcium magnesium acetate, magnesium acetate, magnesium chloride, magnesium propionate, zinc sulfate, zinc chloride, zinc acetate, and combinations thereof.

15. The mucosal adhesive composition according to claim 1(d), wherein the divalent (M... ++ The content of the cation donor is about 1% to about 20% by weight of the total composition.

16. The mucosal adhesive composition according to claim 1(e), wherein the neutralizing agent is a monovalent (M... + ) cations or divalent (M) ++ Salts of cations, wherein the monovalent (M) + ) cations or divalent (M) ++ The cation is selected from calcium (Ca). ++ ), sodium (Na + ), Strontium (Sr) ++ ), Zinc (Zn) ++ ), magnesium (Mg) ++ ), iron (Fe) ++ ), potassium (K) + ), Vanadium (V) ++ ), chromium (Cr) ++ ), manganese (Mn) ++ ), nickel (Ni ++ ), copper (Cu) ++ ), Yttrium (Y ++ ) and its mixtures.

17. The mucosal adhesive composition according to claim 1(e), wherein the neutralizing agent is selected from monovalent (M... + ) cations or divalent (M) ++ Hydroxides of cations, monovalent (M) + ) cations or divalent (M) ++ Phosphates of cations, pyrophosphates of monovalent or divalent cations, hydrogen phosphates of monovalent or divalent cations, carbonates or bicarbonates of monovalent or divalent cations, tripolyphosphates or metaphosphates of monovalent or divalent cations, hydroxides of monovalent or divalent cations, and combinations thereof.

18. The mucosal adhesive composition according to claim 17, wherein the neutralizing agent is selected from sodium hydroxide, sodium metaphosphate, disodium hydrogen phosphate, trisodium phosphate, sodium tripolyphosphate, tetrasodium pyrophosphate, sodium hexametaphosphate, potassium hydroxide, dipotassium hydrogen phosphate, and mixtures thereof.

19. The mucosal adhesive composition according to claim 1(e), wherein the neutralizing agent is present in an amount of about 0.5% by weight to about 20% by weight of the total composition.

20. The mucosal adhesive composition of claim 1, wherein the composition further comprises about 0.5% to about 60% by weight of at least one additional cellulose polymer selected from lower alkyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, divalent cation-modified carboxymethyl cellulose, and mixtures thereof.

21. The mucosal adhesive composition of claim 20, wherein the additional cellulose polymer has a weight-average molecular weight in the range of about 2,000 to about 1,500,000 Daltons.

22. The mucosal adhesive composition of claim 20, wherein the divalent cationic modified carboxymethyl cellulose (CMC) is (i) at least one monovalent (M) + ) cations and at least one divalent (M ++ (i) cation; or (ii) at least one divalent cation functionalized, wherein the divalent cation-modified carboxymethyl cellulose is selected from: (i) Sodium-calcium carboxymethyl cellulose (Na) + -Ca ++ -CMC) (ii) Sodium-magnesium carboxymethyl cellulose (Na) + -Mg ++ -CMC) (iii) Sodium carboxymethyl cellulose-zinc (Na) + -Zn ++ -CMC) (iv) Sodium carboxymethyl cellulose-calcium-zinc (Na) + -Ca ++ -Zn ++ -CMC) (v) Sodium carboxymethyl cellulose-calcium-magnesium (Na) + -Ca ++ -Mg ++ -CMC) (vi) Sodium carboxymethyl cellulose-magnesium-zinc (Na) + -Mg ++ -Zn ++ -CMC) (vii) Sodium carboxymethyl cellulose-tin (Na) + -Sn ++ -CMC) (viii) Sodium carboxymethyl cellulose-calcium-tin (Na) + -Ca ++ -Sn ++ -CMC) (ix) Sodium carboxymethyl cellulose-magnesium-tin (Na) + -Mg ++ -Sn ++ -CMC) (x) Sodium carboxymethyl cellulose-zinc-tin (Na) + -Zn ++ -Sn ++ -CMC) (xi) Carboxymethyl cellulose calcium (Ca ++ -CMC) (xii) Carboxymethyl cellulose magnesium (Mg) ++ -CMC) (xiii) Carboxymethyl cellulose zinc (Zn ++ -CMC) or (xiv) Carboxymethyl cellulose tin (Sn) ++ -CMC).

23. The mucosal adhesive composition of claim 1(f), wherein one or more oral care acceptable ingredients are selected from adhesion promoters, additional modified cellulose ethers, anti-caking agents, antifungal agents, antimicrobial agents, antigingivitis agents, anesthetics, antioxidants, antibiotics, anti-inflammatory agents, adhesives, buffers, pigments, cooling agents, dentin desensitizers, dispersants, enzymes, lubricants, flavorings, fillers, fragrances, gelling agents, humectants, hydrophilic non-oil components, oil carriers, exudation control polymers, preservatives, pigments, plasticizers, analgesics, sweeteners, thickeners, viscosity modifiers, carriers, surfactants, stabilizers, sensory agents, and mixtures thereof.

24. The mucosal adhesive composition of claim 1(f), wherein the content of the one or more oral care acceptable ingredients is from about 0.001% by weight to about 90% by weight of the total composition.

25. The mucosal adhesive composition of claim 1, wherein the lubricant is selected from petrolatum, mineral oil, olive oil, vegetable oil, silicone oil or glycerin, polyethylene glycol, propylene glycol, poly(ethylene oxide-propylene oxide) copolymer, diethylene glycol, triethylene glycol, sorbitol, water, orally acceptable surfactants and mixtures thereof; wherein the lubricant is present in an amount ranging from 0.1% by weight to about 60% by weight of the total oral care ingredients.

26. The mucosal adhesive composition according to claim 1, wherein the colorant is selected from talc, mica, magnesium carbonate, calcium carbonate, magnesium silicate, magnesium aluminum silicate, silicon dioxide, titanium dioxide, zinc oxide, red iron oxide, brown iron oxide, yellow iron oxide, black iron oxide, ferric ammonium ferrocyanide, manganese violet, ultramarine, nylon powder, polyethylene powder, methacrylate powder, polystyrene powder, filament powder, microcrystalline cellulose, starch, titanate mica, iron oxide titanate mica, bismuth oxychloride, and mixtures thereof.

27. The mucosal adhesive composition of claim 1, wherein the flavoring agent is (i) a synthetic flavoring liquid and / or an oil derived from the leaves, flowers and fruits of plants, including vanillin, sage, marjoram, parsley oil, spearmint oil, cinnamon oil, wintergreen oil (methyl salicylate), peppermint oil, clove oil, laurel oil, fennel oil and eucalyptus oil; (ii) an artificial, natural or synthetic fruit flavoring extracted from lemon, orange, banana, grape, lime, apricot and grapefruit; (iii) a fruit essential oil made from apple, strawberry, cherry, orange and pineapple; (iv) a flavoring derived from beans and nuts including coffee, cocoa, kola nut, peanut, almond; (v) a flavoring adsorbed onto a hydrophilic matrix, such as a "spray-dried" flavoring; and (vi) an encapsulated flavoring.

28. The mucosal adhesive composition of claim 1, wherein the composition has a pH of about 5 to about 8.

29. The mucosal adhesive composition of claim 1, wherein the composition is formulated as an ointment, solid, semi-solid, emulsion, powder, paste, dispersion, gel, or patch.

30. A method for in-situ curing the adhesive composition of claim 1, comprising the following steps: (a) Providing at the application site about 0.01% to about 99.9% by weight of the mucosal adhesive composition of claim 1; (b) In the presence of or introduction of a hydrating agent, via divalent (M ++ In situ release of divalent (M) cation donors during hydration. ++ )cation; (c) Enables divalent cations to mediate crosslinking of lower alkyl vinyl ether-maleic acid copolymers; (d) Forming an interpenetrating polymer network (IPN) of lower alkyl vinyl ether-maleic acid copolymer and carboxymethyl cellulose. (e) Obtain the mucosal adhesive composition of claim 1 after in-situ activation and curing.

31. The method for in-situ curing of a mucosal adhesive composition according to claim 30, wherein the hydrating agent is water or saliva.

32. The mucosal adhesive composition according to claim 1, wherein the mucosal adhesive composition is a denture fixation agent or a denture adhesive composition.

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