US2016250242A1PendingUtilityA1

Hypersulfated disaccharide formulations

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Assignee: OPKO HEALTH INCPriority: Dec 3, 2009Filed: May 13, 2016Published: Sep 1, 2016
Est. expiryDec 3, 2029(~3.4 yrs left)· nominal 20-yr term from priority
Inventors:Tahir Ahmed
A61P 39/02A61P 7/00A61P 7/08A61P 37/08A61P 37/06A61P 9/00A61P 9/08A61P 43/00A61P 27/02A61P 25/08A61P 35/00A61P 29/00A61P 27/16A61P 31/00A61P 27/14A61P 31/06A61P 11/04A61K 47/30A61P 21/02A61K 47/32A61P 1/04A61K 31/7016A61P 17/00A61P 19/02A61P 11/02A61K 9/0053A61P 11/00A61P 11/08A61P 13/12A61P 11/06A61K 2121/00
49
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Claims

Abstract

Hypersulfated disaccharides with utility in asthma or asthma related disorders are disclosed. The compounds are formulated with agents that enhance the oral delivery of the hypersulfated disaccharides. The delivery agents are selected from the group consisting of natural or synthetic polymers having ionic side chains as well as other compounds or types of compounds that improve the bioavailability of the disaccharides relative to delivery of the drug without such agents. The hypersulfated disaccharides are made from heparin or salts thereof.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical formulation comprising
 (i) a compound of formula I and pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, SO 3 H or PO 3 H and provided that at least two of R 1 -R 6  is selected from SO 3 H or PO 3 H and 
         (ii) a delivery agent. 
       
     
     
         2 . The formulation according to  claim 1  wherein at least three of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         3 . The formulation according to  claim 1  wherein at least four of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         4 . The formulation according to  claim 1  wherein at least five of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         5 . The formulation according to  claim 1  wherein R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         6 . A pharmaceutical formulation comprising
 (i) a compound of formula I and pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 4 , R 5  and R 6  are independently selected from H, SO 3 H or PO 3 H and R 3  is independently selected from SO 3 H or PO 3 H and 
         (ii) a delivery agent. 
       
     
     
         7 . A pharmaceutical formulation comprising
 (i) a compound of formula I and pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 5  and R 6  are independently selected from H, SO 3 H or PO 3 H and R 3  and R 4  are independently selected from SO 3 H or PO 3 H and a delivery agent selected from the group consisting of a pharmaceutically acceptable natural or synthetic polymer. 
       
     
     
         8 . A pharmaceutical formulation comprising
 (i) a compound of formula I and pharmaceutically acceptable salts thereof   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 6  are independently selected from H, SO 3 H or PO 3 H and R 3 , R 4  and R 5  are independently selected from SO 3 H or PO 3 H and 
         (ii) a delivery agent. 
       
     
     
         9 . A pharmaceutical formulation comprising
 (i) a compound of formula II   
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof wherein R 1 , R 2 , R 4 , R 5  and R 6  are independently selected from the group consisting of H, SO 3 H or PO 3 H and 
         (ii) a delivery agent. 
       
     
     
         10 . A formulation comprising a compound of formula I having R 1 -R 6  as 
       
         
           
                 
                 
               
                     
                 
                     
                   I 
                 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                     
                 
                     
                 
                 
                 
                 
                 
                 
                 
               
                   R 1   
                   R 2   
                   R 3   
                   R 4   
                   R 5   
                   R 6   
                 
                     
                 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   H 
                 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   H 
                 
                   H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                 
                   H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   H 
                 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   H 
                   —SO 3 H 
                 
                   H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                   —SO 3 H 
                 
                     
                 
             
                
               
               
                
                
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       and pharmaceutically acceptable salts thereof and a delivery agent selected from a hydrophilic polymer. 
     
     
         11 . The formulation according to  claim 10  wherein the hydrophilic polymer is selected from a crosslinked polymer of acrylic acid. 
     
     
         12 . The formulation according to  claim 11  wherein the hydrophilic polymer is selected from Carbopol 934P. 
     
     
         13 . A method of treating or alleviating an inflammatory condition in a mammal in need of treatment thereof comprising administration of
 (i) a pharmaceutically effective amount of a formulation comprising a compound of formula I   
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof wherein R 1 -R 6  are independently selected from SO 3 H, PO 3 H or H and provided that at least two of R 1 -R 6  is SO 3 H or PO 3 H and 
         (ii) a delivery agent. 
       
     
     
         14 . The method according to  claim 13  wherein the delivery agent comprises an additive selected from the group consisting of a pharmaceutically acceptable natural or synthetic polymer. 
     
     
         15 . The method according to  claim 13  wherein at least three of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         16 . The method according to  claim 13  wherein at least four of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         17 . The method according to  claim 13  wherein at least five of R 1 -R 6  is selected from SO 3 H or PO 3 H. 
     
     
         18 . The method according to  claim 13  wherein R 1 -R 6  is selected from SO 3 H and the delivery agent is selected from a water insoluble, hydrophilic swellable polymer. 
     
     
         19 . The method according to  claim 18  wherein the water insoluble, hydrophilic swellable polymer is selected from an acrylic acid polymer. 
     
     
         20 . The method according to  claim 13  wherein the inflammatory condition is selected from pulmonary inflammation such as asthma and/or asthma related pathologies; pneumonia, tuberculosis, rheumatoid arthritis, allergic reactions which impact the pulmonary system, early and late phase responses in asthma and asthma related pathologies, diseases of the small and large airways of the lung, bronchospasm, inflammation, increased mucus production, conditions which involve vasodilation, plasma exudation, recruitment of inflammatory cells such as neutrophils, monocytes, macrophages, lymphocytes and eosinophils and/or release of inflammatory mediators by resident tissue cells (mast cells); conditions or symptoms which are caused by allergens, secondary responses to infections, industrial or occupational exposures, ingestion of certain chemicals or foods, drugs, exercise or vasculitis; conditions or symptoms which involve acute airway inflammation, prolonged airway hyperreactivity, increases in bronchial hyperreactivity, asthmatic exacerbations, hyperresponsiveness; conditions or symptoms which involve the release of inflammatory mediators such as 15-HETE, leukotriene C4, PAF, cationic proteins or eosinophil peroxidases; conditions or symptoms which relate to cutaneous, nasal, ocular or systemic manifestations of late phase allergic responses; clinical diseases of the skin, lung, nose, eye or throat or other organs and which involve allergic mechanisms having an histologic inflammatory component upon antigen challenge; allergic rhinitis, respiratory diseases characterized by seasonal or perennial sneezing; rhinorrhea, conjunctivitis, pharyngitis, intrinsic or extrinsic asthma bronchiale, any inflammatory lung disease, acute chronic bronchitis, pulmonary inflammatory reactions secondary to acute chronic bronchitis, chronic obstructive lung disease (COPD), pulmonary fibrosis, Goodpasture's syndrome, any pulmonary condition in which white blood cells play a role including but not limited to idiopathic pulmonary fibrosis and any other autoimmune lung disease; ear, nose and throat disorders such as acute external otitis, furunculosis and otomycosis of the external ear; respiratory diseases such as traumatic and infectious myringitis, acute eustachian salpingitis, acute serous otitis media, acute and chronic sinitis; extrapulmonary conditions selected from any late-phase reactions and inflammatory response such as allergic rhinitis; allergic dermatitis; allergic conjunctivitis; extrapulmonary diseases where inflammation occurs and/or an inflammatory response plays a major role including inflammatory bowel disease; rheumatoid arthritis and other collagen vascular diseases; glomerulonephritis; inflammatory skin diseases and sarcoidosis and cardiovascular inflammation. 
     
     
         21 . The method according to  claim 13  wherein the mammal in need of treatment thereof is human. 
     
     
         22 . An oral dosage form comprising
 (i) a compound of formula I or a pharmaceutically acceptable salt thereof   
       
         
           
           
               
               
           
         
         wherein R 1 -R 6  are independently selected from SO 3 H, PO 3 H or H and provided that at least two of R 1 -R 6  is SO 3 H or PO 3 H and 
         (ii) a delivery agent.

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