WO2020160344A1 - Traitement de combinaison de diclofénac et d'acide hyaluronique contre la leucoplasie buccale - Google Patents

Traitement de combinaison de diclofénac et d'acide hyaluronique contre la leucoplasie buccale Download PDF

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WO2020160344A1
WO2020160344A1 PCT/US2020/016003 US2020016003W WO2020160344A1 WO 2020160344 A1 WO2020160344 A1 WO 2020160344A1 US 2020016003 W US2020016003 W US 2020016003W WO 2020160344 A1 WO2020160344 A1 WO 2020160344A1
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oral
gel composition
oral gel
patient
leukoplakia
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PCT/US2020/016003
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English (en)
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Eli D. Ehrenpreis
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Ehrenpreis Eli D
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Priority claimed from US16/776,984 external-priority patent/US11633352B2/en
Application filed by Ehrenpreis Eli D filed Critical Ehrenpreis Eli D
Publication of WO2020160344A1 publication Critical patent/WO2020160344A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61C—DENTISTRY; APPARATUS OR METHODS FOR ORAL OR DENTAL HYGIENE
    • A61C19/00—Dental auxiliary appliances
    • A61C19/06—Implements for therapeutic treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Definitions

  • Oral leukoplakia is defined as an abnormal whitish area that presents in the oral mucosa. It is a precursor lesion for the development of oral cancer. Oral leukoplakia can occur in patients at high risk for oral cancer, including those smoking and chewing tobacco, heavy alcohol consumers and chewers of betel nuts. These substances produce irritation and chronic inflammation in areas of oral mucosa which may lead to oral leukoplakia. Even ill-fitting dentures or misaligned teeth that are pressing against adjacent oral mucosa may induce oral leukoplakia via an irritative mechanism. Approximately 1 -2% of the world population has oral leukoplakia. The most common locations of oral leukoplakia in the mouth are the buccal mucosa (76%), alveolar sulcus (19%), and the tongue (5%).
  • a first aspect of the present invention is directed to an aqueous oral gel composition for the treatment of oral leukoplakia, comprising a therapeutically effective amount of a nonsteroidal anti- -inflammatory drug (NS AID) or a pharmaceutically acceptable salt thereof, a therapeutically effective amount of hyaluronic acid or a pharmaceutically acceptable salt thereof, a gellingagent or thickener, a flavoring agent and/or sweetener.
  • the composition may include at least one additional orally acceptable excipient such as a preservative, a colorant, a neutralizing base, and a solubilizing or wetting agent.
  • the NSAID is diclofenac or a pharmaceutically acceptable salt thereof.
  • the oral gel composition comprises a combination of diclofenac or a pharmaceutically acceptable salt thereof in an amount of about 0.1 % to about 15% w/w and hyaluronic acid or a pharmaceutically acceptable salt thereof in the amount of about 0.1% to about 10% w/w.
  • the oral gel composition comprises a combination of diclofenac or a pharmaceutically acceptable salt thereof in an amount of about 0.5% to about 6% w/w and hyaluronic acid or a pharmaceutically acceptable salt thereof in the amount of about 1.0% to about 5% w/w.
  • Another aspect of the present invention is directed to a method of delivering the anti leukoplakia oral gel composition described herein to the mucosal tissue of a patient or subject having oral leukoplakia or who is a risk of developing oral leukoplakia, which comprises: administering a therapeutically effective amount of the oral gel composition to the mucosal tissue or the affected portion thereof.
  • the patient who is at risk of developing oral leukoplakia may be a heavy user of tobacco or alcohol, or may be undergoing an event that subjects to the patient or subject to risk of developing oral leukoplakia, such as poor dental hygiene, in which case the therapeutically effective amount of the anti-leukoplakia oral gel composition may inhibit or delay the onset of oral leukoplakia.
  • the method may include use of an oral device comprising: an oral retention portion that is suitably shaped to be retained in the oral cavity for a predetermined treatment period and a covering portion that has at least one surface that contacts the mucosal tissue or the affected portion thereof being treated with the oral gel composition, which in some embodiments may include the tongue (e.g., ventral surface and one or both sides thereof).
  • an oral device comprising: an oral retention portion that is suitably shaped to be retained in the oral cavity for a predetermined treatment period and a covering portion that has at least one surface that contacts the mucosal tissue or the affected portion thereof being treated with the oral gel composition, which in some embodiments may include the tongue (e.g., ventral surface and one or both sides thereof).
  • the method is practiced with an oral device that comprises: a fitting portion having an arcuate shape corresponding to the dental arche of the patient and at least one covering portion, the covering portion having a respective outer surface, an upper wing portion and a lower wing portion; at least one bite flange extending from an interior surface of the fitting portion; an upper ledge extending from the interior surface of the fitting portion and following the arc of the fitting portion, wherein an upper surface of the upper ledge and an upper surface of the at least one bite flange are continuous with one another, wherein the at least one covering section is more flexible than the fitting portion, and wherein a portion of the respective outer surface of the at least one covering portion is in contact with the portion of the mucosal tissue.
  • the at least one covering portion has a surface that contacts and rests against the tongue (e.g., dorsal, ventral or sides).
  • the method comprises applying the oral gel composition to the portion of the mucosal tissue prior to inserting the device in the mouth of the patient. In some embodiments, the method comprises applying the oral gel composition to the outer surface of the device prior to inserting the device in the mouth of the patient. In some embodiments, the method comprises: applying a first amount of the oral gel composition to the portion of the mucosal tissue; and applying a second amount of the oral gel composition to the outer surface of the device and inserting the device in the mouth of the patient.
  • kits may include an oral gel composition described herein dispensed in a suitable package such as a squeezable tube; a device, comprising a fitting portion having an arcuate shape corresponding to the dental arche of the patient; at least one covering portion defined on the fitting portion, the covering portion having a respective outer surface, an upper wing portion and a lower wing portion; at least one bite flange extending from an interior surface of the fitting portion; and an upper ledge extending from the interior surface of the fitting portion and following the arc of the fitting portion, wherein an upper surface of the upper ledge and an upper surface of the at least one bite flange are continuous with one another, and wherein the at least one covering section is more flexible than the fitting portion, and wherein the at least one covering portion may also have a surface that contacts and rests against the tongue (e.g., dorsal, ventral or sides) and floor of the mouth between the lower teeth and the tongue; and printed instructions on how
  • the kit may also include an applicator (e.g., oral swab, Toothette®, and blu®m oral gel applicator) for applying the medication onto the mucosa that is affected by oral leukoplakia.
  • an applicator e.g., oral swab, Toothette®, and blu®m oral gel applicator
  • Figure 1 is a front perspective view of a leukoplakia treatment device, in accordance with an aspect of the present disclosure
  • Figure 2 is a rear perspective view of the device of Figure 1;
  • Figure 3 is a top view of the device of Figure 1;
  • Figure 4 is a rear perspective view of the device of Figure 1;
  • Figure 5 is a magnified rear perspective view of a portion of the device of Figure 1;
  • Figure 6 is a front view of the device of Figure 1;
  • Figure 7 is a front perspective view of a leukoplakia treatment device, in accordance with another aspect of the present disclosure.
  • Figure 8 is a rear perspective view of the device of Figure 7;
  • Figure 9 is a magnified rear perspective view of a portion of the device of Figure 7.
  • Figure 10 is an inside view of the right portion of the device of Figure 10 which includes a covering portion for the front and lateral portions of the tongue.
  • Figure 11 is an inside view of the right portion of the device of Figure 10 which also shows the portion that covers the area beneath the tongue and floor of the mouth inside of the teeth.
  • Figure 12 is a posterior superior view of the device of Figure 1 1.
  • Figure 13 is a posterior superior view of the device of Figure 10.
  • Figure 14 is a posterior view of the device of Figure 10.
  • Figure 15 is a posterior view of the device of Figure 11. DETAILED DESCRIPTION
  • transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.
  • subject and “patient” are used interchangeably herein and describe a person prone to or at risk of developing oral leukoplakia, or who is suffering from oral leukoplakia.
  • a subject "in need of the treatment” may have been positively diagnosed or otherwise presents with a sufficient number of risk factors, or a sufficient number or combination of signs or symptoms such that a medical professional could diagnose or suspect that the subject was suffering from oral leukoplakia.
  • subjects suffering from, and suspected of suffering from, oral leukoplakia are not necessarily two distinct groups.
  • Patients or subjects who are prone to or at risk of developing oral leukoplakia may have a prior history of cancer of the head and neck or esophagus or may be tobacco chewers or smokers, chewers of betel nuts, users of large amounts of alcohol, or those with a history of oral human papilloma virus (HPV) infection.
  • HPV human papilloma virus
  • the present invention is directed to an aqueous oral gel composition for the treatment of oral leukoplakia comprising a nonsteroidal anti-inflammatory drug (NSAID) or a pharmaceutically acceptable salt thereof, hyaluronic acid or a pharmaceutically acceptable salt thereof, a gelling agent or thickener, a flavoring agent and/or sweetener.
  • the composition may include at least one additional orally acceptable excipient such as a preservative, a, a neutralizing base, and a solubilizing or wetting agent.
  • the NSAID is selected from the group consisting of: aspirin, celecoxib, diclofenac, diflunisal, etodolac, ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin.
  • the NSAID is diclofenac or a pharmaceutically acceptable salt thereof.
  • the amount of diclofenac or a pharmaceutically acceptable salt thereof may vary depending upon factors such as the severity of oral leukoplakia (e.g., its present status); the age, body weight, general health, sex and diet of the subject; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see, for example, Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", 10th Edition, A Gilman, J. Hardman and L. Limbird, eds., McGraw-Hill Press, 155- 173, 2001 ).
  • the amount of diclofenac or a pharmaceutically acceptable salt thereof is about 0.1 % to about 15% w/w, and in some embodiments from about 0.5% to about 6% w/w, based on the total weight of the oral gel composition.
  • the amount of hyaluronic acid or a pharmaceutically acceptable salt thereof may vary depending upon factors such as the severity of oral leukoplakia (e.g., its present status); the age, body weight, general health, sex and diet of the subject; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the amount of hyaluronic acid or a pharmaceutically acceptable salt thereof is about 0.1% to about 10% w/w, and in some embodiments from about 1.0% to about 5 % w/w, based on the total weight of the oral gel composition.
  • the NSAID e.g., diclofenac
  • hyaluronic acid may be in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable in the context of a salt refers to a salt of the compound that does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the compound in salt form may be administered to a subject without causing undesirable biological effects (such as dizziness or gastric upset) or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable salt refers to a product obtained by reaction of the compound of the present invention with a suitable acid or a base.
  • Examples of pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts.
  • suitable inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulf
  • the gelling agents may be natural or synthetic. Hydrophilic gelling agents may be particularly suitable for use in the invention.
  • Representative examples of gelling agents or thickeners that may be suitable for use in the present invention include synthetic hectorite, which is a synthetic colloidal magnesium alkali metal silicate complex clay (commercially available as Laponite® (e.g., CP, SP 2002, or D)), carboxyvinyl polymers (e.g., polycarbophil) commercially available as which may also provide antibacterial properties, poloxamers (e.g., Polox ⁇ ), Irish moss, i-carrageenan, gum tragacanth, starch, polyvinyl alcohol (PVA), polyvinylpyrrolidone, Pentravan ⁇ , hydroxyethylpropyl-cellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g., NatrosolTM), and sodium carboxymethyl cellulose or cellulose gum and coll
  • Amounts of the gelling agent or thickener may vary depending upon several factors that may include the desired viscosity (e.g., about 150 x 10 3 to about 360 x 10 3 cP, and in some embodiments from about 200x1 0 3 to about 300x 10 3 cP). In some embodiments, the amount of gelling agent or thickener is from about 0.2% to about 10% w/w, and in some embodiments from about 2% to about 5% w/w.
  • the gel compositions include water in amounts that generally vary from about 20% to about 80% w/w.
  • suitable flavoring ingredients are those containing structural features and functional groups that are less prone to redox reactions.
  • Sweetening agents which can be used include saccharin, dextrose, levulose and sodium cyclamate. The amount of flavoring and sweetening agents may vary, e.g., in amounts from about 0.005% to about 2% w/w.
  • the oral gel compositions may further include one or more orally acceptable excipients.
  • the oral gel composition may also include a solubilizing or wetting agent which may assist in dissolving the active anti-leukoplakia agents, particularly in the presence of saliva.
  • effective solubilizing agents include humectant polyols such as propylene glycol, dipropylene glycol, PEG 40 or polyethylene glycol of other molecular weights, hydrogenated castor oil, glycerin, PEG 40 hydrogenated castor oil, glycerin, sorbitol, xylitol, butylene glycol, and hexylene glycol cellosolves such as methyl cellosolve and ethyl cellosolve, vegetable oils and waxes containing at least about 12 carbons in a straight chain such as olive oil, castor oil and petrolatum and esters such as amyl acetate, ethyl acetate and benzyl benzoate.
  • humectant polyols such as propylene glycol, dipropylene glyco
  • Lipoil® a penetration enhancing mixture of lecithin and isopropyl palmitate, may also be used as solubilizing agent.
  • the amount of solubilizing agent may vary, e.g., in amounts from about 1.0% to about 20% w/w.
  • the oral gel composition described herein may contain a surface-active agent or surfactant.
  • Surface-active agents may be anionic, nonionic or ampholytic (amphoteric) in nature.
  • anionic surfactants that may be suitable for use in the present invention include water- soluble salts of higher fatty acid monoglyceride of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, alkyl aryl sulfonates such as sodium dodecyl benzene sulfonate, higher alkyl sulfoacetates, higher fatty acid esters of 1 ,2-dihydroxy propane sulfonate, higher fatty esters oftaurine and the substantially saturated higher aliphatic acyl amides oflower aliphatic amino carboxylic acid compounds, such as those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals, and the like.
  • taurines and amides are N-methyl-N-cocoyl taurate, N- methyl-N-oleoyl taurate, N-methyl-N-palmitoyl taurate, N-lauroyl sarcosine, and the sodium, potassium, and ethanolamine salts ofN-lauroyl, N-myristoyl, orN-palmitoyl sarcosine which should be substantially free from soap or similar higher fatty acid material.
  • nonnionic surfactants that may be suitable for use in the present invention include condensation products of ethylene oxide with various reactive hydrogen- containing compounds reactive therewith having long hydrophobic chains (e.g., aliphatic chains of about 12 to 20 carbon atoms), which condensation products (“ethoxamers”) contain hydrophilic polyoxyethylene moieties, such as condensation products ofpoly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g., sorbitan monosterate) and polypropyleneoxide (e.g., Pluronic® materials).
  • condensation products of ethylene oxide with various reactive hydrogen- containing compounds reactive therewith having long hydrophobic chains e.g., aliphatic chains of about 12 to 20 carbon atoms
  • condensation products ethoxamers
  • hydrophilic polyoxyethylene moieties such as condensation products ofpoly(ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g.,
  • ampholytic surfactants that may be suitable for use in the present invention include derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be a straight chain or branched and wherein one of the aliphatic substituents contains from about 8 to about 18 carbon atoms and one contains an anionic water-solubilizing group, e.g ⁇ , carboxylate, sulfonate, sulfate, phosphate, or phosphonate.
  • suitable amphoteric surfactants are betaines, specifically cocam idopropyl betaine. Mixtures of amphoteric surfactants can also be employed.
  • Nonionic and amphoteric surfactants are disclosed by Gieske et al., U.S. Patent 4,051 ,234.
  • Surface active agents or surfactants are typically present in amount of about 0.1 % to about 5% by weight, and in some embodiments from about 0.7% to about 2% by weight, based on the total weight of the composition.
  • the gel compositions may include a preservative.
  • Suitable preservatives include sodium benzoate, benzoic acid, diazolinyl urea, imidazolinyl urea, benzalkonium chloride, parabens, chlorhexidine acetate, chlorhexidine gluconate, citric acid, sorbic acid, potassium sorbitol, ethanol, dichlorobenzyl alcohol, chlorbutanol and phenoxyethanol.
  • Suitable preservatives are typically present in amount of about 0.01 % to about 0.5% by weight, based on the total weight of the composition.
  • the gel compositions may include a colorant. Any one of commercially available FDA approved colorants may be used. Examples of colorants include titanium dioxide, Acid Blue 9, FD&C Green 3, FD&C Red 3 and FD&C Red 4. Colorants are typically present in amount of about 0. 10% to about 5% by weight, and in some embodiments from about 0.5% to about 2% by weight, based on the total weight of the composition.
  • the gel compositions may include a neutralizing base to adjust pH to about 6 to about 8.
  • Sodium hydroxide is an example of neutralizing base.
  • the oral gel composition may include diclofenac USP 3.6 g (3% w/w), hyaluronic acid 240 mg (0.2% w/w), ethanol 200 proof 4.8 mL, Lipoil® 28.8 mL, Polox® 20% gel q.s. ad (as much as is sufficient) 120 g, peppermint oil 2 mL, and Acid Blue 9 to the desired color.
  • the oral get composition may include diclofenac 3 g (3% w/w), hyaluronic 0.2% (200 mg), Pentravan ⁇ q.s. ad 90 g, water 9 g, xylitol 7.5% (9 g), polyethelyene glycol to form paste, Acid Blue 9 to desired color and 0.5 ml 0.2% peppermint oil or oil of spearmint.
  • the oral gel composition may include diclofenac 3 g (3% w/w), glycerin 4 g, sodium saccharate 50 mg, peppermint oil 0.02 mL, 0.2% hyaluronic acid 20 mg (0.2% w/w) and hydroxyethylcellulose 2% gel 100 g.
  • Oral gels of the present invention may be prepared in accordance with standard techniques.
  • the term, "therapeutically effective amount” refers to an amount of the oral gel composition and the active agents therein that i s/are effective in producing the desired therapeutic response in a particular patient suffering from oral leukoplakia.
  • the term "therapeutically effective amount” thus includes the amount of the oral gel composition and the active agents therein that when administered, may induce a positive modification in oral leukoplakia, or is sufficient to prevent development or progression of oral leukoplakia, or alleviate to some extent, one or more of the symptoms of oral leukoplakia, orwhich simply kills or inhibits the growth of diseased cells.
  • Another aspect of the present invention is directed to a method of delivering the oral gel composition described herein to the mucosal tissue of a patient or subject or an affected portion thereof, which comprises: administering a therapeutically effective amount of the oral gel composition to the mucosal tissue or an affected portion thereof which comprises; inserting, in the mouth of the patient, a device comprising: an oral retention portion that is suitably shaped to be retained in the oral cavity for a predetermined treatment period and a covering portion that has at least one surface that contacts the mucosal tissue being treated with the oral gel composition.
  • the combination of the anti-leukoplakia oral gel composition described herein, and the device may increase the retention time of the active agents on the affected mucosal tissue, which in turn may enhance the efficacy of the agent.
  • the oral gel composition may be administered topically in the mouth, followed by placement of the device that is brought into direct contact with and covers the treated mucosal tissue.
  • the oral gel may be applied to or coated onto, the device beforehand. This approach may also provide a more targeted delivery of the agent to the affected mucosal tissue, as well as an increase in retention time.
  • the oral gel composition may be applied to the affected tissue, followed by insertion of the device having additional oral gel composition dispersed therein.
  • the device is configured so as to be comfortably held in the mouth for prolonged periods of time and therefore extend the contact time of the oral gel composition or active agents therein on the oral mucosa or affected portions thereof.
  • the present methods may provide one or more advantages such as an increase in the concentration and duration of contact of the oral gel composition described herein with the area(s) of mucosa that is/are, or could be affected with oral leukoplakia; a decrease in systemic toxicity of the active agents since the agents may be administered in lower doses that will remain within the oral cavity longer and will, therefore, have lower systemic absorption from being swallowed; and further an increase in topical pharmacologic activity at the site of release, i.e., the oral mucosa, compared to conventional methods of direct delivery of substances onto the oral mucosa such as spray and gel forms of these medications.
  • Subject II applied the same topical gel form of diclofenac 3%, 0.2% hyaluronic acid and 7.5% xylitol in an inert incipient three times daily to an area of the right buccal mucosa and wore a prototype device for 20 minutes following each application, for 3 days.
  • Subject I reported experiencing a sensation of dryness in the buccal mucosa at the area of application for 1 hour after use for the first 3 days, and no other side effects. This dry sensation was no longer present after three days.
  • Subject 2 reported a tingling of the lips for 30 seconds on expectorating the gel, but no other side effects. Visual inspection of the areas of topical application in both subjects showed no change from the topical medication.
  • Devices suitable for use in the present methods may have several individual components. They may be manufactured using a one mold or involve several separate parts.
  • the first component of the device is an oral retention or fitting portion that functions to comfortably hold the device in the mouth by fitting over the teeth where it can be held for a predetermined period of time of treatment.
  • the fitting portion of the device may fit over the upper teeth, the lower teeth, both the upper and lower teeth, or a portion of either or both the upper or lowerteeth. This portion of the device may be pre-constructed to fit any size mouth. It is anticipated that several sizes of the device will be constructed to accommodate patients with larger or smaller mouth sizes, enhanced gag reflexes or oral pain.
  • the device may be made of a pliable material that can be fitted to the specific patient, either by the patient or by a medical professional such as a dentist.
  • This portion of the device may be constructed of materials that will fit the needs of the device in terms of biocompatibility, ease of device cleaning, and the stability of the material within the mouth.
  • the fitting portion may be made using materials, e.g., poly (methyl methacrylate), silicone rubber, polyurethane, and co-polymers of vinyl acetate or ethylene.
  • Other materials include polyvinylacetate-polyethylene or ethylene vinyl acetate (EVA) copolymer, polyvinylchloride, latex rubber, acrylic resin and other laminated or non-laminated thermoplastics.
  • the materials for construction may also include a dual layering of a soft material on the inside portion and a hard acrylic outside portion that holds the device firmly to the teeth and forms a protective shell for the device.
  • One or more other covering portions of the device are designed to fit or cover at least the major parts of the mouth that are affected by the oral disease or disorder.
  • These covering portions of the device may be constructed of soft materials that rest gently along the mucosa (lining) of the cheeks (called the buccal mucosa), the inner portions of the lips, the tongue (e.g., the ventral and sides), the palate and the mucosa underneath the tongue.
  • These portions of the device may be constructed of materials such as silicone rubber, latex, synthetic polyisoprene, nitrile, polyurethane resin, plastic, polyester, acrylic resin pads, polypropylene, low density polyethylene, and various laminates or layered soft/soft laminates.
  • laminates may feature a top layer of denser vinyl for memory and abrasion resistance and a soft pliable bottom layer for patient comfort.
  • the covering portion of the device may include an additional layer of semi-porous material that will be in contact with the oral mucosa. This will allow for anti-leukoplakia agents (e.g., the oral gel composition described herein) to be placed or disposed on the device, so they may be gradually released onto the affected tissue.
  • anti-leukoplakia agents e.g., the oral gel composition described herein
  • Representative examples of materials that may be used for this part of v the device include materials used for wound dressings such as thin, semi-permeable polyurethane films coated with a layer of acrylic adhesive.
  • Other materials, such as gels may be incorporated into the mucosal (i.e., inner) side of the covering portion of the device. The use of gels allows a soft, generally water-soluble material to adhere to this portion of the device.
  • Active agents such as antibiotics and local pain relieving drugs can be mixed into or incorporated into the matrix of the gels.
  • examples of such gels include carboxymethylcellulose-based gels and alginate- based gels.
  • the inner portion may include foam-like materials. Foam materials provide a soft interface with the affected oral mucosa. Active agents may be held within the matrix of these foam-like materials.
  • the material used for the internal layer of the covering portion of the device that is in contact with the mucosa may include drug-eluting fibers. These may include monolithic polymer fibers and reservoir fibers such as polyactic acid (PLLA) in which the drug is dissolved or dispersed.
  • PLLA polyactic acid
  • Nanoporous materials such as ceramics, composites, metals, and polymeric organic substances.
  • Other examples of materials include nanoporous oxides, including alumina, titania, silica, zirconia, polycarbonate, polyethylene terephthalate, polysulfi de and polymers combined with ceramics.
  • Nanoporous materials may be produced by anodization, lithography, focused ion beam etching, ion-tracking etching, phase separation and sol-gel processes.
  • the covering portions of the device may contain ridges, indentations or an abrade surface that will allow topical medication to remain for a longer period of time within the device when in contact with the affected mucosa.
  • the device may have an upper part that fits on upper teeth (e.g., upper front teeth) and has a covering portion that drapes across the palate and the inner part of the upper lip.
  • the device may have a lower part that fits on lower teeth (i.e., lower front teeth) and has a covering portion that drapes across the sublingual mucosa, the sides and/or underportion of the tongue, and inner portions of the cheek (the buccal mucosa).
  • Devices may also have adjustable components that allow the device to fit snugly and comfortably in the mouth of an affected patient.
  • both the upper and lower parts of the device may contain a system that allows for adjustment of these portions of the device to fit comfortably in the mouth. Adjustments can be made to shorten or lengthen the device as well as to elevate of lower the device to assist with fitting of the apparatus for comfortable and prolonged use.
  • Additional modifications of the device may be made in order to optimize fitting in the mouth and for individualizing the construction of the device based on the patient's oral anatomy. Such modifications may be made with the use of imaging methods such as radiographic procedures and 3- dimensional photographic imaging. Furthermore, the use of dental-type molds may be used to optimize sizing of the device for individual patients. Yet further modifications may include addition of materials such as padding and anchoring portions of the device to add to the comfort level of its use. Other modifications may be made based on methods to size the individual portions of the device to optimize covering of the affected area of the oral mucosa. Further modifications may be performed to allow the device to be worn overnight. The device will be constructed in multiple sizes, with appropriate adjustment of the dimensions of its individual components to accommodate patients with smaller and larger mouths, heightened gag reflexes and sensitivity to devices that are placed in the mouth.
  • the device is designed such that covering portions of the device that are designed for the coverage of areas of the mucosa that are not affected in an individual patient can be removed by the cutting these portions away. This will increase the comfort of wearing the device.
  • the active agents may be applied to the covering portion(s) of the device that come into contact with the affected mucosal tissue.
  • the medications may be first applied to the affected area(s), followed by placement of the device in the mouth. Using this method, the device holds the medications in place and allows their prolonged contact with the mucosa.
  • An oral treatment device 200 as shown in Figure 1 , in accordance with an aspect of the present disclosure, is suitable for use with the methods described herein.
  • the device 200 may have several individual components or portions, however, it should be noted that "component” does not necessarily mean a separate piece or pieces unless specifically set forth as such.
  • the device 200 includes a curved, or arcuate, oral retention or fitting portion or body 204 that can be comfortably held for a predetermined period of time or treatment.
  • the fitting portion 204 of the device 200 has an arc that generally corresponds to the arrangement of teeth in the human mouth, i.e., the dental arche, and may fit over the upper teeth, the lower teeth, both the upper and lower teeth or a portion of either or both the upper or lower teeth.
  • the device 200 may be preconstructed to fit any size mouth. Alternatively, it may be made of a pliable material that can be fitted to the specific patient, either by the patient or by a medical professional such as a dentist.
  • the device 200 may be constructed of materials that meet biocompatibility requirements for human use, ease of device cleaning and the stability of the material within the mouth.
  • the device 200 may be made using materials including, silicone rubber, poly (methyl methacrylate), polyurethane and co-polymers of vinyl acetate or ethylene.
  • Other materials that could be used include polyvinylacetate-polyethylene or ethylene vinyl acetate (EVA) copolymer, polyvinylchloride, latex rubber, acrylic resin and other laminated or non-laminated thermoplastics.
  • the device 200 includes symmetrically provided covering portions 208, each having an upper wing portion 212 and a lower wing portion 216 configured to fit or cover parts of the mouth that are affected by leukoplakia.
  • These covering portions 208 of the device 200 are generally more flexible (e.g., compliant or softer) than the body portion 204 by, for example, being thinner than the body portion 204 or being of a different material.
  • the covering portions 208 may rest along the sensitive mucosa (lining) of the cheeks (called the buccal mucosa), the inner portions of the lips, the palate and the mucosa to the sides of and underneath the tongue. T hese areas may contain ridges or surface indentations to prolong adherence of topical medications.
  • covering portions 208 of the device 200 may be constructed of materials, in addition to those materials listed above, such as silicone rubber, latex, synthetic polyisoprene, nitrile, polyurethane resin, silicone rubber, plastic, polyester, acrylic resin pads, silicone, polypropylene, low density polyethylene and various laminates or layered soft/soft laminates.
  • laminates may feature a top layer of denser vinyl for memory and abrasion resistance and a soft pliable bottom layer for patient comfort.
  • the choice of materials for the device 200 provides a predetermined amount of "spring load” that urges the covering portions 208 outward as represented by the arrows A in Figure 3.
  • the covering portions 208 of the device 200 have an exterior surface 220 that may include an additional layer 224 of semi-porous material that will be in contact with the oral mucosa.
  • This semi-porous layer 224 will allow for anti-leukoplakia agents to be placed or disposed on the device 200, in order to be gradually released onto the affected tissue.
  • Representative examples of materials that may be used for this part of the device include materials used for wound dressings such as thin, semi-permeable polyurethane films coated with a layer of acrylic adhesive.
  • gels may be incorporated onto the exterior surface 220 of the covering portion 208 of the device 200.
  • the use of gels allows a soft, generally water-soluble material to adhere to this portion of the device 200.
  • Medications such as antibiotics and local pain relieving drugs can be mixed into or incorporated into the matrix of the gels.
  • examples of such gels include carboxymethylcellulose-based gels and alginate-based gels.
  • each covering portion 208 and its respective upper and lower wing portions 212, 216 are made of softer or more flexible material, as set forth above.
  • the upper wing portions 212 extend above the upper gum line to cover or contact a portion of the upper inner cheek, and the inner upper lip, whi le the lower wing portions 2 1 6 extend below the lower gum line to cover or contact a portion of the lower inner cheek.
  • the upper and lower wing portions 212, 21 6 cover the openings for the parotid duct and a number of salivary glands.
  • a portion of the external surface 220 may be treated to provide a micro-textured surface 240 that results in small reservoirs being created, as shown in Figure 1.
  • the micro-textured surface 240 may be provided in the device 200 by etching a pattern into the mold that is used to make the device 200.
  • the external surface 220 of the device 200 may be modified by etching or sand-blasting once freed from the mold.
  • These small reservoirs serve to retain in place therapeutic materials (e.g., the oral gel composition described herein) that have been applied to the inner cheek to treat leukoplakia.
  • the medicine is then in place longer before it is washed away by saliva.
  • the therapeutic material may be "loaded" onto the micro-textured surface 220 before the device 200 is placed in the mouth which may aid in application to the inner mucosa.
  • the covering portion 208 may include foam-like materials.
  • Foam materials provide a soft interface with the affected oral mucosa.
  • Medications e.g., the oral gel composition described herein may be held within the matrix of these foam-like materials.
  • the material used for the exterior surface 220 of the covering portions 208 of the device 200 that is in contact with the mucosa may include drug-eluting fibers.
  • These fibers may include monolithic polymer fibers and reservoir fibers such as polylactic acid in which the drug is dissolved or dispersed.
  • nanoporous materials such as ceramics, composites, metals and polymeric organic substances.
  • materials include nanoporous oxides, including alumina, titania, silica, zirconia, polycarbonate, polyethylene terephthalate, polysulfide and polymers combined with ceramics.
  • Nanoporous materials may be produced by anodization, lithography, focused ion beam etching, ion-tracking etching, phase separation and sol-gel processes.
  • the body portion 204 includes an upper portion configured to cover the mucosa between the upper teeth and the gums and the inside of the upper inner lip.
  • this aids in retention of the device 200 within the mouth by holding it in place between the upper inner lips and upper teeth.
  • the device may be worn to over the lower teeth and gums and the inside of the lower lip.
  • This portion is constructed of thinner or more pliable material for comfort and for holding medication in place in that area of the mouth.
  • the device 200 may include symmetrically opposed bite flanges 230 that extend from an interior surface 304.
  • an upper ledge 308 also extends from the interior surface 304 and when the device 200 is placed in the mouth of a patient, the upper teeth of the patient may rest thereon.
  • the upper ledge 308 is continuous around an inner arc of the device 200 and is contiguous with an upper bite surface 312 of the bite flanges 230.
  • Each bite flange 230 includes a lower bite surface 504 that, in conjunction with the upper bite surface 312, forms a wedge shape.
  • the top teeth will rest on the upper ledge 308 and some of the upper and lower back teeth, e.g., mid-molars, can bite down on the upper and lower bite surfaces 312, 504 of the bite flange 230. In this manner, the device 200 can be held in place with minimal effort.
  • the bite flange 230 is designed for comfort to allow the patient to bite down on the device without becoming fatigued too quickly during the time that the medication is held in place.
  • symmetric lower tabs 508 are provided forward of each respective bite flange 230.
  • the lower tabs 508 rest on some of the lower teeth forward of those that are biting down on the bite flanges 230.
  • the lower tabs 508 provide additional stability and absorb some stress from the patient holding on, biting down, on the bite flanges 230.
  • the lower tabs 508 may extend around a portion of the arc of the lower teeth. In another embodiment, the lower tabs 508 may extend all the way around the arc into a single lower tab, i.e., a continuous piece for all of the lower teeth to contact.
  • FIG. 7 another leukoplakia treatment device 800, in accordance with an aspect of the present disclosure that is suitable for use with the methods described herein is presented from a front perspective view.
  • the device 800 is similar to the device 200 as set forth above, however, the device 800 includes symmetrically opposed bite flanges 830 that differfrom the bite flanges 230 described above.
  • the bite flanges 830 extend from an interior surface 904.
  • An upper ledge 908 also extends from the interior surface 904 and when the device 800 is placed in the mouth of a patient, the upper teeth of the patient may rest thereon.
  • the upper ledge 908 is continuous around an inner arc of the device 800 and is contiguous with an upper bite surface 912 of the bite flanges 830.
  • Each bite flange 830 includes a lower bite surface 916.
  • each bite flange 830 is made of softer or spongier material that the patient can bite down on without becoming fatigued too quickly.
  • the bite flange 830 includes a guide ridge 920 that is generally transvers to the upper and lower bite surfaces 912, 916.
  • the guide ridge 920 provides a space to line up the upper teeth in order to maintain the device 800 in position.
  • the patient need not bite down on the bite flange 830 to keep the device 800 in place in the mouth with the side portions positioned against the inner cheeks.
  • FIGs 10-15 illustrate a device that is a modified version of Fig. 7 and which includes a covering portion for the front and lateral portions of the tongue.
  • Figure 10 is an inside view of the right portion of the device.
  • This form of the device includes a soft covering portion (850) for the lateral and front of the tongue that follows the arcuate design of the device.
  • This soft covering portion for the lateral tongue is attached to the inferior portion of the bite flange (830), is a thicker depth than the covering wings.
  • Part 850 rests comfortably and wraps around the lateral portions of the tongue, forming a covering over the sides and front of the tongue.
  • Figure 1 1 is an inside view of the right portion of the modified device.
  • This form of the device includes a soft covering portion (850) for the lateral and front of the tongue that is attached to the inferior part of the bite flanges (830) and follows the arcuate design of the device. It also shows the portion (880) that covers the area beneath the tongue and floor of the mouth inside of the teeth.
  • This is a wing like portion of the device with similar thin structure and fits under the tongue. It is attached to both the inferior portion of the bite flanges (830) and to the inferior portion of the lateral tongue covering portion (850) of the device.
  • the tongue can be slipped into combined portions (850) and (880), thus providing coverage of the lateral tongue, the ventral tongue and the mucosa of the floor of the mouth inside of the teeth.
  • Figure 12 is a posterior superior view of the device of Figure 1 1.
  • This view demonstrates the soft covering portion (850) for the later and front of the tongue that is attached to the inferior part of the bite flanges (830) and follows the arcuate design of the device. It also shows the portion (880) that covers the area beneath the tongue and floor of the mouth inside of the teeth.
  • This is a wing-like portion of the device and has a similar thin structure to the cheek and inner lip covering wings and fits under the tongue. It is attached to both the inferior portion of the bite flanges (830) and to the inferior portion of the lateral tongue covering portion (850) of the device.
  • Figure 13 is a posterior superior view of the device of Figure 10. This view shows the soft covering portion (850) for the lateral and front of the tongue that is attached to the inferior part of the bite flanges (830) and follows the arcuate design of the device.
  • Figure 14 is a posterior view of the device of Figure 10. This view demonstrates the soft covering portion (850) for the lateral and front of the tongue that is attached to the inferior part of the bite flanges (830) and follows the arcuate design of the device. This design allows portion (850) to easily rest on the sides and front of the tongue.
  • Figure 15 is also a posterior view of the device of Figure 1 1.
  • This view demonstrates the soft covering portion (850) for the later and front of the tongue that is attached to the inferior part of the bite flanges (830) and follows the arcuate design of the device. It also shows the portion (880) that covers the area beneath the tongue and floor of the mouth inside of the teeth.
  • This is a wing-like portion of the device has a similar thin structure to the cheek and inner lip wings and fits under the tongue. It is attached to both the inferior portion of the bite flanges and to the inferior portion of the lateral tongue covering portion (850) of the device.
  • Additional modifications of the device may be made in order to optimize fitting in the mouth and for individualizing the construction of the device based on the patient's oral anatomy. Individualization can be accomplished by the construction of devices in several sizes to accommodate patients with different size mouths and abilities to tolerate the presence of an oral device inside of the mouth. Further modifications may be made with the use of imaging methods such as radiographic procedures and 3-dimensional photographic imaging. Furthermore, the use of dental-type molds may be used to optimize sizing of the device for individual patients. Yet further modifications may include addition of materials such as padding and anchoring portions of the device to add to the comfort level of its use. Other modifications may be made based on methods to size the individual portions of the device to optimize covering of the affected area of the oral mucosa.
  • the designs of the devices described above follow the contour of the mouth for comfort.
  • the bite flanges provide surfaces for both the upper and lower teeth to close on and hold the device in place.
  • the device is configured to be located over only the upper teeth as this provides additional comfort compared to devices that fit over both the upper and lower teeth, in addition to making it easier for the patient to breathe while the device is in place.
  • a device where only the upper teeth are covered allows for easy elimination of saliva without the necessity to remove the device.
  • the device may be worn to fit only the lower teeth with similar benefits.
  • the side portions between teeth, gums and inner lips provide coverage of gums, upper oral mucosa and inside of upper lip and a portion of the lower lip allowing for increased mucosal coverage and which also helps to hold the device in place.
  • the device may worn so that the side portions cover the gums, lower oral mucosa and inside of the lower lip.
  • Bolstering of the mouth is an additional feature that promotes retention of topical medications used for the treatment of oral leukoplakia.
  • the active (e.g., the oral gel composition described herein) agents may be applied to the covering portion(s) of the device that come into contact with the affected mucosal tissue.
  • the use of semi-porous materials to line these portions of the device, imparts sustained release properties to the device that allow for gradual and prolonged exposure of the mucosa to the agents.
  • the medications e.g., the oral gel composition described herein
  • the device holds the medications in place and allows their prolonged contact with the mucosa.
  • the oral gel composition described herein remains in contact with the oral mucosa that is affected by leukoplakia for a predetermined time or treatment period which for purposes of the present invention, may include a contact time of 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, or more.
  • methods entail the device being held in the mouth for about IO minutes to up to 2 hours at a time. The method may be conducted multiple times per day, for example, but not limited to, from 1 -4 times daily.
  • the oral gel composition described herein is topically administered to mucosal tissue in a therapeutically effective amount.
  • this amount will vary depending upon the agent itself and other factors which may include one or more ofthe severity factors of the condition and the general health of the patient.
  • the therapeutic amount may be effective to ameliorate one or more symptoms presented by the patient, e.g., mucosal redness, abnormal white mucosa, and oral ulcerations, or even cure the condition.
  • the oral gel composition described herein is topically applied to mucosal tissue of a patient suitably prior to an event that is known to induce oral leukoplakia, e.g., poor dental hygiene, in a prophylactically effective amount.
  • This amount may be effective to delay or inhibit the onset of leukoplakia or reduce the severity or duration of leukoplakia or any symptom associated therewith, or even preventing the onset of the condition.
  • Representative examples of patients or subjects who are prone to or at risk of developing oral leukoplakia include persons who may have a prior history of cancer of the head and neck or esophagus or may be heavy users of tobacco products (chew, cigarettes and cigars), users oflarge amounts of alcohol, chewers of betel nuts, or those with a history of oral HPV infection.
  • prophylactically effective amounts will vary depending upon factors which may include one or more of the severity of the condition and the general health of the patient.
  • kits for administering the oral gel composition described herein to the mucosal tissue of an individual may include a device, as described above, one or more dosage amounts of the oral gel composition which may be disposed in a container such as a squeezable tube, an applicator (e.g., oral swab, Toothette®, and blu®m oral gel applicator) to more accurately apply the medication onto the mucosa that is affected by oral leukoplakia and instructions regarding the method of using the device and the agent to treat the affected mucosal tissue area.
  • an applicator e.g., oral swab, Toothette®, and blu®m oral gel applicator

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Abstract

Une composition de gel buccal appropriée pour le traitement de la leucoplasie buccale comprend une combinaison de diclofénac avec de l'acide hyaluronique et des procédés d'administration du gel buccal qui peut comprendre un dispositif qui prolonge le temps de contact du gel buccal avec les zones de la muqueuse qui sont affectées par la leucoplasie buccale.
PCT/US2020/016003 2019-02-01 2020-01-31 Traitement de combinaison de diclofénac et d'acide hyaluronique contre la leucoplasie buccale WO2020160344A1 (fr)

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US201962800151P 2019-02-01 2019-02-01
US62/800,151 2019-02-01
US16/776,984 US11633352B2 (en) 2018-01-09 2020-01-30 Diclofenac and hyaluronic acid combination treatment for oral leukpoplakia
US16/776,984 2020-01-30

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WO2019139863A1 (fr) * 2018-01-09 2019-07-18 E2Bio Life Sciences, Llc Procédé et dispositif d'amélioration de traitements topiques contre la mucosite buccale et d'autres affections buccales

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WO1997003699A1 (fr) * 1995-07-18 1997-02-06 Hyal Pharmaceutical Corporation Utilisation d'acide hyaluronique et d'un nsaid pour la fabrication d'un medicament destine au traitement des affections des muqueuses
US20040005277A1 (en) * 2002-07-02 2004-01-08 Willison Michael P. Device and method for delivering an oral care agent
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