Classifications

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  • A61K36/18—Magnoliophyta (angiosperms)
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  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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• • A—HUMAN NECESSITIES
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  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• • A—HUMAN NECESSITIES
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• • A—HUMAN NECESSITIES
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  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0041—Mammary glands, e.g. breasts, udder; Intramammary administration
• • A—HUMAN NECESSITIES
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  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
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  • A61K9/0058—Chewing gums
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
  • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
  • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
  • C07K14/4725—Proteoglycans, e.g. aggreccan
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2317/00—Immunoglobulins specific features
  • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
  • C07K2317/41—Glycosylation, sialylation, or fucosylation

Definitions

• the present invention relates to the uses of the protein PRG4 (including proteoglycans thereof) and/or therapeutic modulation thereof.
• the present invention relates compositions and methods thereof, including, surgical lubrication, athletic lubrication, treatment of diseases associated with compromised boundary lubrication in the oral cavity, a dermal filler, methods of drug delivery, and for nursing lubrication.
• the proteoglycan 4 (prg4) gene codes for highly glycosylated proteins termed megakaryocyte stimulating factor (MSF), lubricin, and superficial zone protein (SZP).
• MSF megakaryocyte stimulating factor
• SZP superficial zone protein
• Lubricin was first isolated from synovial fluid and demonstrated lubricating ability in vitro similar to synovial fluid at a cartilage-glass interface. Lubricin was later identified as a product of synovial fibroblasts. O-linked ⁇ (l-3)Gal-GalNAc oligosaccharides within a large mucin like domain of 940 amino acids, encoded for by exon 6, have also been described.
• SZP was first localized at the surface of explant cartilage from the superficial zone and isolated from conditioned medium.
• the present invention provides, in various embodiments, compositions, and methods of use thereof, for managing lubrication.
• lubrication includes, by way of non-limiting example, use as a surgical lubricant, use in a treatment for prevention or reduction of post- surgical adhesions, use in a treatment for oral ulcerations, use as an athletic lubricating patch, use as a dermal filler, use in a treatment for dry mouth, use in a drug delivery method or composition, and use in nursing lubrication.
• PRG4 protein e.g., purified or isolated PRG4 protein for use in the treatment of any of the aforementioned disorders (or any other disorder described herein).
• compositions and methods are provided for the therapeutic replenishment and enrichment of boundary lubricant molecules in the oral cavity.
• Described in certain embodiments of the present invention is the observation that PRG4 mRNA is expressed in mouse Submandibular tissue, indicating that PRG4 protein is secreted into the oral cavity.
• Figure 1 illustrates PRG4 mRNA expression in various mouse submandibular glands. Amplified samples were screened for the presence of PRG4 products by using agarose gel electrophoresis. Vertical lanes 11-16 contain amplified, verified PRG4 mRNA from submandibular gland tissues of 6 different mice.
• the PRG4 protein protects the oral cavity (including the throat) against significant shear forces generated during eating, talking, swallowing, speaking and/or other oral functions. Further described in certain instances of the present invention is the observation that the molecular mechanisms of boundary lubrication found in cartilage, including the ability of secreted components to mediate shear stress in the presence of dynamic loading, are likely useful when utilized for lubricating the oral cavity.
• the oral care composition of the present invention further comprises, various oil extracts, sweeteners, salivary gland stimulators, preservatives and flavorings.
• the oral care composition further comprises a therapeutically effective amount of sodium hyaluronate.
• the oral care composition will further comprise a local anesthetic such as lidocaine, lignocaine or prilocaine.
• the present invention provides a method for treating xerostomia, or symptoms associated therewith (including symptoms of xerostomia associated with Sjogren's syndrome, allergy, oral surface disorders, chronic inflammation, hyperosmolarity, aging, prescription or OTC drugs, radiation therapy, chemotherapy, nerve damage or any combination thereof) comprising topically administering to the oral cavity (or an ulcer within the oral cavity) in an individual in need thereof, an effective amount of any oral care composition described herein.
• the present invention provides a method for treating oral ulcerations comprising topically administering to an oral cavity ulcer in an individual in need thereof, an effective amount of the oral care composition of the present invention.
• any lubricant composition described herein further comprises one or more antiseptics selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, cetyl trimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, alcohol, sodium chloride and sodium bicarbonate.
• one or more antiseptics selected from the group consisting of chlorhexidine gluconate, benzalkonium chloride, cetyl trimethylammonium bromide, cetylpyridinium chloride, benzethonium chloride, alcohol, sodium chloride and sodium bicarbonate.
• Some embodiments of the present invention provide a method of preventing or reducing friction during ambulatory motion comprising the application of any suitable lubricating composition described herein (e.g., an aqueous gel, sol, solution, or adhesive patch containing PRG4) to the area of interest.
• the composition e.g., adhesive patch
• the composition further comprises hyaluronic acid.
• the composition e.g., adhesive patch
• the composition further comprises a residence time increasing polymer, excipient or demulcent.
• any dermatological composition of the present invention further comprises a dermato logically effective amount of collagen, carboxymethyl cellulose, polyethylene glycol and/or polyethylene oxide.
• any dermatological composition of the present invention further comprises a drug selected from the group consisting of antithrombogenic drugs, anti-inflammatory drugs, hormones, chemotactic factors, analgesics, growth factors, cytokines, osteogenic factors and anesthetics.
• any dermatological composition of the present invention further comprises retinoic acid and/or deuterium reduced water.
• Some embodiments of the present invention provide a method for restoring of tissue volume, skin turgor, texture and tightness in the skin (e.g., in the face or selected areas of the body) of a person comprising the steps of injecting a dermatological composition of the present invention into the dermis, or the hypodermis.
• treatment and injection may occur at one or more areas of the face, or selected areas of the body of a person, including, but not limited to, the peri-orbital area, the lips, the malar area, the nasolabial folds, the labio-mandibular folds, the neck, or the hands.
• Certain embodiments of the present invention provide a method of providing (e.g., facilitating) drug delivery, the method comprising delivering a bioactive agent to an individual, the bioactive agent being delivered in a composition comprising: an admixture of a bioactive agent and a carrier comprising PRG4.
• the bioactive agent comprises a drug, a peptide, a protein, an antibody or fragment thereof, a nucleic acid, or imaging agent.
• the delivery carrier further comprises sodium hyaluronate.
• the delivery carrier further comprises a surface active phospholipid selected from the group consisting of L- ⁇ -dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine and sphingomyelin.
• the physical delivery of the admixture can be accomplished via by topical administration, injection, or orally, or by any other suitable administration technique.
• Some embodiments of the present invention provide a method of preventing or reducing friction during nursing (breastfeeding) comprising applying to a surface in need thereof (e.g., a nipple, areola and/or breast) any lubricating composition described herein (e.g., an aqueous gel, sol, solution, or adhesive patch) containing PRG4.
• a surface in need thereof e.g., a nipple, areola and/or breast
• any lubricating composition described herein e.g., an aqueous gel, sol, solution, or adhesive patch
• any composition described herein e.g., adhesive patch
• any composition e.g., adhesive patch
• any composition e.g., adhesive patch
• any composition further comprises a residence time increasing polymer, excipient or demulcent.
• Figure 1 illustrates mouse PRG4 mRNA expression, as demonstrated by agarose electrophoresis following amplification in Submandibular gland tissue. mRNA was verified through sequencing.
• Figure 2 illustrates an amino acid sequence of PRG4 as well as nucleic acid primer sequences for PCR amplification of the PRG4 mRNA.
• PRG4 is a member of the mucin family, which are generally abundant on epithelial linings and provide many functions, including lubrication and protection from invading microorganisms.
• the functional properties of mucins are generally determined by specialized glycosylation patterns and their ability to form multimers through intermolecular disulfide bonds, both of which are altered in chronic diseases (e.g. cystic fibrosis, asthma).
• Biochemical characterization of PRG4 isolated from synovial fluid showed molecular heterogeneity in O- glycosylation, which appears to mediate lubricating properties.
• Physicochemical modes of lubrication have been classified as fluid film or boundary.
• the operative lubrication modes depend on the normal and tangential forces on the articulating tissues, on the relative rate of tangential motion between these surfaces, and on the time history of both loading and motion.
• the friction coefficient, ⁇ provides a quantitative measure, and is defined as the ratio of tangential friction force to the normal force.
• One type of fluid-mediated lubrication mode is hydrostatic. At the onset of loading and typically for a prolonged duration, interstitial fluid becomes pressurized, due to the biphasic nature of tissue; fluid may also be forced into the asperities between articular surfaces through a weeping mechanism.
• the relevant extent to which fluid pressure/film versus boundary lubrication occurs depends on a number of factors.
• lubricant film can flow between the conforming sliding surfaces, which can deform elastically, elastohydrodynamic lubrication occurs.
• Pressure, surface roughness, and relative sliding velocity determine when full fluid lubrication begins to break down and the lubrication enters new regimes.
• lubricant films adherent to the articulating surfaces begin to contribute and a mixed regime of lubrication occurs. If the velocity decreases even further and only an ultra- thin lubricant layer composed of a few molecules remain, boundary lubrication occurs.
• this mode may be important because the opposing tissue surface make contact over -10% of the total area, and this may be where most of the friction occurs.
• lubricant-coated surfaces bear an increasingly higher portion of the load relative to pressurized fluid, and consequently, this mode can become increasingly dominant.
• boundary lubrication mitigates stick-slip, and is therefore manifest as decreased resistance both to steady motion and the start-up of motion. In some instances, the latter situation is relevant to load bearing surfaces after prolonged compressive loading (e.g., sitting or standing in vivo).
• Typical wear patterns of articular surfaces such as in cartilage, also illustrate that in some instances, boundary lubrication is important for the protection and maintenance of the tissue structure.
• the loading of the oral cavity is subject to (e.g., dominated by) shear forces, with chewing generating significant stress upon surface cells and tooth enamel.
• routine shear stress may also pose a strong degradatory and inflammatory risk.
• Severe atrophy or iatrogenically caused dryness from cancer treatments such as tamoxifen, antihistamines, anti-depressants, or high blood pressure medication may also make normal levels of shear stress painful.
• the accumulation of PRG4 within fluid between articulating surfaces, as well as its propensity to spontaneously bind to tissue matrix contribute to PRG4's boundary lubricating ability.
• the PRG4 protein is administered in an oral care composition (e.g., a pharmaceutically acceptable oral care composition).
• the administered PRG4 protein is an exogenous PRG4 protein (i.e., PRG4 that is not native to the individual to whom it is being administered).
• an orally acceptable formulation e.g., an oral care product described herein
• any composition described herein further comprises a therapeutically effective amount of sodium hyaluronate.
• Xerostomia is a condition in which the salivary glands do not produce sufficient quantities of saliva.
• xerostomia causes discomfort which can in some cases be quite severe. Without saliva, the mouth may burn and the throat and tongue can undergo radical changes. Teeth can decay rapidly and the tongue can become smooth, cracked and vulnerable to infection. There is often a loss of taste and, because saliva contains important digestive enzymes, there are often problems with digestion.
• the mouth is one of the body areas most exposed to the external environment. Normally, mucous forms a continuous protective layer in the nose, mouth and throat. A patient suffering from xerostomia not only has decreased fluid in the mouth, but may also have an insufficient quantity of mucoproteins and mucopolysaccharides to hold fluid in contact with the cells and create a barrier to irritation and infection.
• PRG4 protein e.g., an oral care composition comprising PRG4 protein in an effective amount and/or concentration.
• the composition is administered as an aqueous solution (or suspension) of PRG4.
• the composition will further comprise yerba santa fluid extract, citrus oil, lemon oil, lime oil, neroli oil, orange oil, a mint oil, peppermint oil, spearmint oil, anise oil, cardamom oil, cinnamon oil, clove oil, coriander oil, eucalyptus oil, fennel oil, lemongrass oil, nutmeg oil, eriodictyon fluid extract, or glycyrrhiza extract in the range of 0.25 wt.% to 10 wt.%, more preferably 0.5 wt.% to 5.0 wt.%, and most preferably about 1.25 wt.%.
• the composition will further comprise one or more sweeteners, in total comprising about 1.0 wt.% to 30 wt.%, more preferably 10 wt.% to 20 wt.%, most preferably about 15 wt.% sweetener.
• Suitable sweeteners may be readily selected, and the amount of sweetener incorporated into the present composition will be determined by taste.
• the sweetener may be any compound or compounds that cause sweetness or intensify sweetness.
• the sweetener may be of naturally occurring or synthetic origin, and may have nutritive or non-nutritive value.
• suitable sweeteners include: the saccharides, e.g., fructose, glucose, glycerose, threose, erythrose, methylpentose, galactose, xylose, ribose, dextrose, maltose and d-mannose; sugar alcohols such as sorbitol, xylitol and mannitol; water- soluble artificial sweeteners such as the soluble saccharin salts, e.g., sodium or calcium saccharin, cyclamate salts, acesulfame-K, and the like; and dipeptide-based sweeteners such as L-aspartyl-L-phenylalanine methyl ester.
• saccharides e.g., fructose, glucose, glycerose, threose, erythrose, methylpentose, galactose, xylose, ribose, dextrose,
• sweeteners are set forth in the Encyclopedia of Chemical Technology, vol. 19, 2d Ed., New York: John Wiley & Sons, 1969, at pp. 593-607.
• Preferred sweeteners are noncariogenic, and particularly preferred sweeteners for use herein are xylitol, sorbitol, mannitol, sodium saccharin, and combinations thereof.
• composition also contain a "stimulator" compound which will stimulate salivary gland secretion.
• a particularly preferred compound for this purpose is citric acid, present in an amount ranging from about 0.25 wt.% to about 5.0 wt.%, preferably about 0.5 wt.%. Incorporation of citric acid into the present composition also serves to provide a pleasant, citrus flavor.
• the composition contain one or more preservatives, typically an anti-oxidant present in an amount effective to retard oxidation and/or inactivation of the fluid extract.
• preservatives typically an anti-oxidant present in an amount effective to retard oxidation and/or inactivation of the fluid extract.
• suitable preservatives include ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, potassium or sodium sorbate, sodium bisulfite, sodium metabisulf ⁇ te, sorbic acid, sulfur dioxide, and sodium or potassium benzoate.
• a particularly preferred preservative for use herein is sodium benzoate.
• coloring agents which may be either natural or synthetic, flavoring agents, flavor preserving agents, diluting agents, emulsifying agents, excipients, pH buffering agents, and the like.
• Suitable colorants include dyes that are generally suitable for food, drug and cosmetic applications, i.e., those known as F. D. & C. dyes. Acceptable dyes should be water soluble. Illustrative examples include the disodium salt of 5,5-indigotindisulfonic acid ("F.D. & C. Blue No. 2.") and the monosodium salt of 4-[4-N-ethyl-p-sulfo- benzylamino)diphenylmethylene]-[l-(N-ethyl-N-p-sulfon ium-benzyl)-2,5 - cyclohexadienimine ("F.D. & C. Green No. 1 "). Reference may be had to the Kirk-Othmer Encyclopedia of Chemical Technology, 3rd Ed., in Volume 6, for further F.D.& C. colorants and corresponding chemical structures.
• Flavorings are optional, as incorporation of citric and/or ascorbic acids into the composition will in the absence of any additional flavoring agents provide a pleasant, citrus flavor.
• Additional flavorings may include other natural or artificial flavors, e.g., mint oils such as peppermint, wintergreen (methyl salicylate), spearmint, eucalyptus, etc., citrus oils such as lemon oil, orange oil, lime oil, grapefruit oil, fruit essences such as apple essence, peach essence, raspberry essence, and the like.
• mint oils such as peppermint, wintergreen (methyl salicylate), spearmint, eucalyptus, etc.
• citrus oils such as lemon oil, orange oil, lime oil, grapefruit oil, fruit essences such as apple essence, peach essence, raspberry essence, and the like.
• an oil-based flavoring agent is selected, one or more preservatives will be included in the composition as described above.
• Various synthetic flavors may also incorporated into the composition.
• the flavoring agent(s) will be present in
• the oral care composition further comprises enzymes found in saliva including lactoperoxidase, thiocyanate and glucoseoxidase.
• the composition as just described is preferably administered as an aqueous solution, gel or paste and administered via a mouthspray, mouthwash, toothpaste, rinse or gel.
• the composition may also be prepared as a gum or lozenge, with the preferred components and the preferred relative composition by weight the same as in the above- described aqueous solution.
• gum compositions are prepared using any suitable conventional method.
• the PRG4 is admixed with a chewable gum base, one or more sweeteners, and optional additional components as described hereinabove, present in the above-described proportions.
• a gum composition described herein comprises flavoring additives, emulsifying agents, and coloring agents as described herein.
• the "gum base” may be one of a number of types of compositions, and is typically prepared by heating and blending various ingredients, e.g., natural gums, synthetic resins, waxes, plasticizers, etc.
• ingredients found in a chewing gum base include masticatory substances of vegetable origin such as chicle, crown gum, nispero, rosidinha, jelutong, pendare, perillo, niger gutta, tunu, etc., masticatory substances of synthetic origin such as butadiene-styrene polymer, isobutyleneisoprene copolymer, paraffin, petroleum wax, polyethylene, polyisobutylene, polyvinylacetate, etc., plasticizers or softeners such as lanolin, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glycerine, etc.
• Lozenges described herein are optionally shaped solids containing the PRG4 in a candy or glycerinated gelatin base.
• lozenge forms are prepared, for example, using suitable methods described in Remington's Pharmaceutical Sciences.
• the PRG4 is mixed with sweetener and other optional compounds as described above, and the resulting syrup is concentrated and the mixture shaped and/or compressed, while heating, into the desired form.
• the amount of PRG4 administered may vary and be dependent on the subject being treated, the severity of the xerostomia, and the judgment of the prescribing health care professional.
• an effective dosage regimen will typically be 1-2 tsp (or 1-20 mL, 2- 15 mL, 3-10 mL, or the like) of an aqueous composition (or the equivalent in gum or lozenge form) given orally once or 2-6 times per day.
• the aqueous composition it is preferred that the composition be retained in contact with the oral mucosa for a time sufficient to allow coating of the interior of the mouth with the PRG4. It is preferred that the composition be retained in the mouth for 1-30, 2-20, 5-15, or 8-10 seconds.
• the composition may be, and may be administered as, a mouthwash, where the mouth is simply rinsed with the aqueous solution, or if desired, the composition may be swallowed.
• any oral care composition as described herein is suitable to benefit or useful for treating patients suffering from ulcerations inside the mouth, whether the common "canker sore" or the more serious ulceration often seen as a side effect of cancer therapy described as oral mucositis.
• the method and composition is directed to a medication that is topically administered to the lesion.
• the composition of the present invention provides prolonged relief of the pain and discomfort associated with canker sores.
• the composition for treating oral ulcerations comprises topically administering PRG4 in an orally acceptable solution to the oral ulcer in need thereof.
• the PRG4 composition further comprises sodium hyaluronate.
• the PRG4 composition further comprises one or more local anesthetics selected from the group consisting of lidocaine, lignocaine and prilocaine.
• the present invention further provides a method for treating oral ulcerations comprising topically administering to the oral ulcer in need thereof, an effective amount PRG4 in a orally acceptable solution (or in any other composition envisioned herein) wherein said composition is in the form of a gel, liquid, cream, ointment, spray or viscous solution.
• compositions suitable for lubrication of instruments and/or other surfaces involved in surgical or medical procedures are provided herein.
• a viscoelastic solution (or suspension) comprising PRG4 and/or sodium hyaluronate and, optionally, additional excipients and demulcents.
• such compositions are biocompatible aqueous solutions (or suspensions) that are very particularly suitable as surgical auxiliaries and/or temporary implants.
• compositions e.g., solutions
• surgical/medical lubricants for use in the insertion of catheters, endoscopes, surgical instruments, gloves into body orifices, as surgical auxiliaries and/or temporary implants, as hydration implants, and for use in cataract extraction, photokeratectomy, intraocular lens (IOL) insertion and removal, corneal surgery, glaucoma surgery, trauma surgery, posterior segment surgery, ocular plastic surgery and muscle surgery.
• RTM. currently marketed by Bausch & Lomb, Vitrax.RTM., currently marketed by A.M.O., and Viscorneal.RTM. and Biocorneal.RTM., marketed by the Applicant, which contain sodium hyaluronate (NaHA); Orcolon.RTM., from Optical Radiation Corporation, which contained a polyacrylamide and is now unavailable; and Occucoat.RTM., from Storz, which contains hydroxypropyl methyl cellulose (HPMC).
• NaHA sodium hyaluronate
• Orcolon.RTM. from Optical Radiation Corporation
• HPMC hydroxypropyl methyl cellulose
• the surgical lubricant/viscoelastic fluid is comprised of PRG4 in a surgically acceptable salt solution.
• the surgical lubricant/viscoelastic fluid further comprises sodium hyaluronate.
• the surgical lubricant/viscoelastic fluid further comprises additional excipients and demulcents, including but not limited to carboxymethylcellulose sodium, hydroxyethyl cellulose, hypromellose, methylcellulose, dextran 70, gelatin, glycerin, polyethylene glycol 300, polyethylene glycol 400, polysorbate 80, propylene glycol, polyvinyl alcohol and povidone.
• the present invention further provides a method of providing lubrication for use in surgical or medical procedures comprising the application of an effective amount PRG4 (e.g., in a surgically acceptable solution or in any other composition envisioned herein) to tissue or a medical device in need thereof.
• PRG4 e.g., in a surgically acceptable solution or in any other composition envisioned herein
• Such methods are methods of reducing or preventing tissue damage associated with the surgical or medical procedure.
• Such surgical or medical procedures include the insertion of catheters, endoscopes, surgical instruments, gloves into body orifices, as surgical auxiliaries and/or temporary implants, as hydration implants, cataract extraction, photokeratectomy, intraocular lens (IOL) insertion and removal, corneal surgery, glaucoma surgery, trauma surgery, posterior segment surgery, ocular plastic surgery and muscle surgery.
• IOL intraocular lens
• the present invention also provides, in certain embodiments, novel compositions and methods of reducing friction during ambulatory motion, such methods comprising administering any composition (e.g., any composition comprising PRG4 protein) to a surface in need thereof (such as a chafed surface or a surface susceptible to friction and/or chafing).
• a composition e.g., any composition comprising PRG4 protein
• Athletic endeavors often include significant shear stress and friction between skin and clothing, skin and skin, and hair and skin. This often leads to chafing, "chub rub,” skin lacerations, bleeding from the nipples, and so forth.
• This type of shear induced insult is common during long distance competitions such as marathons or ironman races.
• Current approaches include the application of polymers and skin moisturizers such as BODYGLIDE. However current approaches fail to provided long lasting relief and do not provide any mechanism of reducing boundary lubrication.
• the present invention provides an athletic composition for use in reducing friction caused by ambulatory motion comprising PRG4.
• the PRG4 is formulated with or in a delayed release polymer.
• the delayed release polymers comprises one or more of the following, carboxymethylcellulose, hydroxypropylmethylcellulose, polypropylene, or other common excipients or demulcents.
• the athletic composition further comprises sodium hyaluronate.
• the athletic composition further comprises Allantoin (0.5%)
• the athletic composition further comprises Aloe (Aloe).
• Leaf Extract C18 36 Acid Triglyceride, Capric/Caprylic Stearic Triglyceride,
• an adhesive patch is coated with PRG4 and is placed between the area of friction and the cause of friction.
• a suitable adhesive patch include band-aid or athletic tape.
• hyaluronic acid and PRG4 are contained within the adhesive patch.
• the present invention further provides a method of reducing friction during motion comprising the application of an effective amount PRG4 in a solution, gel, sol (or in any other composition or device envisioned herein) to the area in need thereof.
• the present invention provides injectable compositions for injection into the dermis or the hypodermis (subcutaneous tissue) to restore age related tissue loss in the face, and selected areas of the body, such as neck and hands.
• the use of PRG4 in a dermal filler formulation increases the amount of time the dermal filler is retained prior to absorption.
• Facial aging occurs as the result of several factors, e.g.: inherent changes within the skin, effects of gravity, facial muscles acting on the skin (dynamic lines), soft tissue loss or shift and bone loss and loss of tissue elasticity. The skin ages when the epidermis begins to thin, causing the junction with the dermis to flatten.
• Collagen decreases as a person ages and the bundles of collagen, which gives the skin turgor, become looser and lose strength. When the skin loses elasticity, it is less able to resist stretching. Coupled with gravity, muscle pull and tissue changes, the skin begin to wrinkle. Water loss and breakdown of bonds between cells also reduces the barrier function of the skin, which can cause the skin's pore size to increases.
• the face loses volume, soft tissue, and fat.
• the appearance of jowls and folds are usually caused by the drooping of facial tissues and folding of areas where the muscles below are attached to the skin. As part of the reduction in soft tissue the face gets more hollow.
• Nasolabial folds are the lines that run from the sides of the nose to the corners of the mouth. These folds have been treated with facial fillers.
• the nose area As a person ages, the nose elongates. Common causes of elongation are thinning of the soft tissue and loss of elasticity, which causes "drooping of the tip" and unmasking of the bone, creating a new hump.
• the lower face area As the face ages, facial tissues descend. This results in the so-called “laugh lines”. Folds and lines in this area have been treated with facial fillers.
• jowls form when the cheeks sag around a fixed point along the jaw where the facial muscles attach to the jawbone.
• the facial muscles continue down into the neck as a sheet called the platysma muscle. This muscle often gaps in the center of the neck, creating two bands.
• injectable collagen has been used for restoring tissue loss in the face. Since the 1980s, injectable collagen has been used as a soft-tissue filler to fill wrinkles, lines and scars on the face.
• Collagen is a naturally occurring protein that supports various parts of the body including skin, tendons and ligaments.
• Fat injections have been used for years to add volume, fill wrinkles, lines and enhance the lips. Fat injections involve taking fat from one part of the patient's body (abdomen, thighs or buttocks) and reinjecting it beneath the facial skin. Botulinum toxins have been used for neck spasms, cranial nerve disorders and eye spasms. With the recent FDA approval of Botox for cosmetic use in the glabellar region, the drug is used to smooth wrinkles. When injected into facial muscles botulinum toxins block nerve impulses, temporarily paralyzing muscles and smoothing wrinkles.
• Hyaluronic acid is one of most commonly used cosmetic dermal filler which adds volume to minimize wrinkles and lines.
• Hyaluronic acid is a linear polysaccharide that exists naturally in all living organisms and is a universal component of the extra-cellular spaces of body tissues. The identical structure of hyaluronic acid in all species and tissues makes this polysaccharide an ideal substance for use as a bio-material in health and medicine.
• Hyaluronic acid is present in many places in the human body. It gives volume to the skin, shape to the eyes and elasticity to the joints. The highest concentrations are found in connective tissues, and most hyaluronic acid (about 56%) is found in the skin.
• hyaluronic acid Various forms of hyaluronic acid are provided commercially by a number of manufacturers.
• the most commonly used hyaluronic acid is the non-animal stabilized hyaluronic acid (NASHA) in a clear gel form, produced by bacterial fermentation from streptococci bacteria.
• NASHA non-animal stabilized hyaluronic acid
• the non-animal derived hyaluronic acid is free from animal proteins. This limits the risk of animal based disease transmissions or development of allergic reactions to animal proteins.
• the most known non- animal stabilized hyaluronic acid is manufactured by Q-med, Seminariegatan, Uppsala, and commercially available under the tradename Resty lane. RTM..
• the injectable composition comprises PRG4 in a viscous solution. In one further embodiment, the injectable composition comprises PRG4 in combination with a dermato logically effective amount of hyaluronic acid. In yet another embodiment, the injectable composition comprises PRG4 in combination with a dermatologically effective amount of collagen, carboxymethyl cellulose, polyethylene glycol and/or polyethylene oxide.
• the injectable composition comprises PRG4 in combination with a drug selected from the group consisting of antithrombogenic drugs, anti-inflammatory drugs, hormones, chemotactic factors, analgesics, growth factors, cytokines, osteogenic factors and anesthetics.
• the injectable composition comprises PRG4 in combination with retinoic acid and/or deuterium reduced water.
• present invention provides a method of drug delivery, the method comprising a bioactive agent in combination with (e.g., admixed) with PRG4 protein.
• a bioactive agent is delivered to a subject, and delivered in a composition comprising: a bioactive agent admixed with a carrier comprising PRG4.
• Carrier materials for drug delivery of pharmaceuticals are based on a broad range of materials, such as organic or inorganic polymers, metals and ceramics. Without being bound to any theory it is believed that the use of PRG4 as a drug delivery method will result in increased residence time and superior localization of target compounds.
• the bioactive agent comprises a drug, a peptide, a protein, an antibody or fragment thereof, a nucleic acid, or imaging agent.
• the delivery carrier further comprises sodium hyaluronate.
• the delivery carrier further comprises a surface active phospholipid selected from the group consisting of L- ⁇ -dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine and sphingomyelin.
• the physical delivery of the admixture can be accomplished via by topical administration, injection, or orally.
• the present invention provides a method of lubrication for nursing mothers, said method comprising administering to a surface in need thereof PRG4 protein.
• PRG4 boundary lubrication which operates in a single monolayer, offers superior residence time without the residue that other creams create.
• the nursing lubricant is comprised of PRG4 in an aqueous solution, gel, sol, or adhesive patch.
• the lubricant further comprises sodium hyaluronate.
• the lubricant comprises additional excipients and demulcents.
• PRG4 As used herein, the term "PRG4", "PRG4 protein” or “proteoglycan 4" protein, is used interchangeably with the term “lubricin” protein.
• PRG4 is used herein also to encompass the term megakaryocyte stimulating factor (MSF), that has been accepted for the UCL/HGNC/HUGO Human Gene Nomenclature data base, and superficial zone protein (SZP).
• MSF megakaryocyte stimulating factor
• SZP superficial zone protein
• the PRG4 or lubricin protein (used interchangeably herein with lubricin proteoglycan) as used herein refers to any isolated or purified native or recombinant lubricin proteins, homologs, functional fragments or motifs, isoforms, and/or mutants thereof.
• the isolated or purified PRG4 protein comprises an amino acid sequence for a human native or recombinant lubricin protein.
• the isolated or purified PRG4 protein comprises an amino acid sequence encoded by prg4 gene exons that encode the full length PRG4 protein or isoforms' primary structures.
• the proteoglycan 4 (prg4) gene contains 12 exons.
• the PRG4 protein used herein comprises an amino acid sequence encoded by prg4 gene exons 1-12, more preferably, exons 6-12, and most preferably, exons 9-12. [0087]
• the PRG4 protein includes any PRG4 proteins now known, or later described.
• a preferred PRG4 protein amino acid sequence is provided in SEQ ID NO:1.
• the PRG4 protein shares the primary amino acid structure of any known PRG4 proteins or iso forms with at least 60% homology, preferably 75% homology, more preferably 85%, 90%, 95%, 96%, 97%, 98%, 99% or more homology.
• a preferred PRG4 protein has an average molar mass of between 50 kDa and 400 kDa, comprising one or more biological active portions of the PRG4 protein, or functional fragments, such as a lubricating fragment, or a homolog thereof.
• the PRG4 protein comprises a biological active portion of the protein.
• the language "substantially free of cellular material” includes preparations of a PRG4 protein having less than about 30% (by dry weight) of other proteins (also referred to herein as a "contaminating protein”), more preferably less than about 20%, still more preferably less than about 10%, and most preferably less than about 5% of other proteins.
• a PRG4 protein having less than about 30% (by dry weight) of other proteins (also referred to herein as a "contaminating protein”), more preferably less than about 20%, still more preferably less than about 10%, and most preferably less than about 5% of other proteins.
• culture medium represents less than about 20%, more preferably less than about 10%, and most preferably less than about 5% of the volume of the preparation of the protein of interest.
• An aqueous solution of the above formula is made by mixing together the ingredients listed above to make a finished product that is suitable for injection.
• a lubricating cream containing PRG4 is applied to areas of sensitivity, pain or dryness subsequent to breastfeeding.

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