Applications of partially and fully sulfated hyaluronan

Abstract

Described herein is the use of partially and fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof for therapeutic and cosmetic applications as well as the treatment of a number of systemic, dermatological, periodontal, ophthalmic, and urological inflammatory diseases.

1 . A method for reducing or preventing inflammation in a subject comprising administering to the subject an effective amount of a partially or fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof, or a combination thereof. 
     
     
         2 . The method of  claim 1 , wherein at least one primary C-6 hydroxyl proton of the N-acetyl-glucosamine residue is substituted with a sulfate group. 
     
     
         3 . The method of  claim 1 , wherein at least 1% of the primary C-6 hydroxyl protons of the N-acetyl-glucosamine residue of hyaluronan are substituted with a sulfate group. 
     
     
         4 . The method of  claim 1 , wherein from 1% to 100% of the primary C-6 hydroxyl protons of the N-acetyl-glucosamine residue of hyaluronan are substituted with a sulfate group. 
     
     
         5 . The method of  claim 1 , wherein at least one C-2 hydroxyl proton or C-3 hydroxyl proton of a uronic acid residue or at least one C-4 hydroxyl proton of an N-acetyl-glucosamine residue is substituted with a sulfate group. 
     
     
         6 . The method of  claim 1 , wherein at least one C-2 hydroxyl proton and C-3 hydroxyl proton of a uronic acid residue and at least one C-4 hydroxyl proton of an N-acetyl-glucosamine residue is substituted with a sulfate group. 
     
     
         7 . The method of  claim 1 , wherein the compound has a degree of sulfation from 0.1 to 4.0 per disaccharide unit. 
     
     
         8 . The method of  claim 1 , wherein the partially or fully sulfated hyaluronan has an average molecular size of less than 10 kDa. 
     
     
         9 . The method of  claim 1 , wherein the partially or fully sulfated hyaluronan has an average molecular size from 0.5 kDa to 10 kDa. 
     
     
         10 . The method of  claim 1 , wherein the hyaluronan is not derived from an animal source. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutically acceptable ester is a prodrug. 
     
     
         12 . The method of  claim 1 , wherein the partially or fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof is administered as a pharmaceutical composition, wherein the composition optional further comprises an anti-inflammatory agent, an anti-pyretic agent, steroidal and non-steroidal drugs for anti-inflammatory use, a hormone, a growth factor, a contraceptive agent, an antiviral, an antibacterial, an antifungal, an analgesics, a hypnotic, a sedative, a tranquilizer, an anti-convulsant, a muscle relaxant, a local anesthetic, an antispasmodic, an antiulcer drug, a peptidic agonist, a sympathiomimetic agent, a cardiovascular agent, an antitumor agent, or an oligonucleotide. 
     
     
         13 . The method of  claim 12 , wherein the composition comprises a capsule, a tablet, a chewing gum, a lozenge, a powder, or a beverage. 
     
     
         14 . The method of  claim 12 , wherein the composition is administered intravenously, intramuscularly, subcutaneously, intra-articularly, ophthalmically, vaginally, rectally, intranasally, by ingestion, topically or applied directly to the oral mucosa, gingival, or periodontal pocket. 
     
     
         15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the pharmaceutically acceptable salt comprises an organic salt, a metal salt, or a combination thereof. 
     
     
         17 . The method of  claim 1 , wherein the pharmaceutically acceptable salt comprises a salt selected from the group consisting of NH 4   + , Na + , Li + , K + , Ca +2 , Mg +2 , Fe +2 , Fe +3 , Cu +2 , Al +3 , Zn +2 , 2-trimethylethanolammonium cation (choline), or a quaternary salt of isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, arginine, and histidine. 
     
     
         18 . The method of  claim 1 , wherein the partially or fully sulfated hyaluronan is produced by reacting hyaluronan with pyridine-sulfur trioxide, and wherein the partially or fully sulfated hyaluronan comprises a pyridinium adduct. 
     
     
         19 . The method of  claim 18 , wherein the partially or fully sulfated hyaluronan comprising the pyridinium adduct have a molecular weight of less than or equal to 10 kDa. 
     
     
         20 . The method of  claim 1  wherein the inflammation is produced by cancer, multiple sclerosis, osteoarthritis, rheumatoid arthritis, Alzheimer's beta amyloid peptide, periodontal disease, gingivitis, peri-implantitis, diabetic nephropathy, inflammatory bowel disease, asthma, rhinitis, rhinosinusitis, chronic obstructive pulmonary disease, acute lung injury, cystic fibrosis, sickle cell anemia, a cardiovascular inflammatory disorder, a pulmonary inflammatory disorder, an ocular inflammatory disorder, a cerebral inflammatory disorder or an intestinal inflammatory disorder. 
     
     
         21 . A method for treating or preventing an ophthalmological condition, a genitourinary condition, a respiratory condition, a cardiovascular condition, a gastrointestinal disease, a rheumatological and immunological disease, a renal disease, a degenerative joint disease, a dental or oral disease, or a neurological disease, the method comprising administering to a subject a partially or fully sulfated hyaluronan. 
     
     
         22 . (canceled) 
     
     
         23 . A method for treating or preventing a skin disorder comprising applying an effective amount of a partially or fully sulfated hyaluronan on the surface of the skin. 
     
     
         24 . The method of  claim 23 , wherein the skin disorder comprises rosacea, atopic dermatitis (eczema), allergic contact dermatitis, psoriasis, dermatitis herpetiformis, acne, diabetic skin ulcers and other diabetic wounds, burns, sunburn, prevention of scarring, actinic keratoses, inflammation from insect bites, poison ivy, radiation-induced dermatitis/burn, interstitial cystitis, photo-dermal ageing, or seborrheic dermatitis. 
     
     
         25 . An oral care product comprising an effective amount of a partially or fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof. 
     
     
         26 . The product of  claim 25 , wherein the product comprises a gel, paste, rinse, or a device comprising a coating of the partially or fully sulfated hyaluronan. 
     
     
         27 . The product of  claim 26 , wherein the device is floss, a periodontal brush, or periodontal probe. 
     
     
         28 . A method for treating or preventing an eye disorder comprising administering to the eye an effective amount of a partially or fully sulfated hyaluronan. 
     
     
         29 . The method of  claim 28 , wherein the eye disorder comprises age-related macular degeneration, diabetic retinopathy, dry eye syndrome, conjunctivitis, iritis, uveitis, allergic conjunctivitis, or corneal inflammation and scarring. 
     
     
         30 . The method of  claim 28 , wherein the compound is administered intraocularly or to the surface of the eye. 
     
     
         31 . A method for treating or preventing urological inflammation in a subject comprising administering to the subject an effective amount of a partially or fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof. 
     
     
         32 . The method of  claim 31 , wherein the urological inflammation comprises inflammation of the bladder, urethra, urothelium lining, kidney, prostate, vagina, uterus, or any combination thereof. 
     
     
         33 . The method of  claim 31 , wherein the composition is administered intravenously, intramuscularly, subcutaneously, by ingestion, or transmucosally. 
     
     
         34 . The method of  claim 31 , wherein the composition is administered transmucosally, wherein the transmucosal administration comprises transbuccal, sublingual, oral, vaginal, intranasal, rectal, or by intravesical instillation. 
     
     
         35 . A method for reducing or inhibiting the activity of P-selectin and/or L-selectin; reducing or inhibiting the activation of RAGE by one of its diverse ligands; reducing or inhibiting the activity of human leukocyte elastase; or reducing or inhibiting the activity of a cationic polypeptide, comprising administering to a subject a partially or fully sulfated hyaluronan. 
     
     
         36 . (canceled) 
     
     
         37 . The method of  claim 35 , wherein the ligand is an AGE product, HMGB1, or a S100 family ligand. 
     
     
         38 . (canceled) 
     
     
         39 . (canceled) 
     
     
         40 . The method of  claim 21 , wherein the dental or oral disease is gingivitis or anaphthous ulcer. 
     
     
         41 . A method for preventing infection in a subject comprising administering to the subject an effective amount of a partially or fully sulfated hyaluronan or the pharmaceutically acceptable salt or ester thereof, or a combination thereof. 
     
     
         42 . The method of  claim 41 , wherein the infection is a bacterial infection. 
     
     
         43 . The method of  claim 41 , wherein the infection is caused by Gram positive bacteria or Gram negative bacteria. 
     
     
         44 . The method of  claim 41 , wherein the infection is caused by  Streptococcus pneumoniae, Hemophilus influenzae, Staphylococcus, Mycoplasma pneumoniae , or  Chlamydial pneumoniae.