Combination Of Local And Systemic Therapies For Enhanced Treatment of Dermatologic Conditions

Abstract

A treatment for inflammatory dermatoses, such as psoriasis and atopic dermatitis (eczema), is disclosed that utilizes topical administration of a halogenated xanthene, such as rose bengal, together with administration of one or more complementary targeted systemic dermatology therapies, preferably a therapy that addresses the inflammatory pathway and is other than an NSAID that is a COX-1 and/or COX-2 inhibitor. Examples of complementary targeted systemic therapeutic ingredients include: corticosteroids, including betamethasone dipropionate and fluocinonide; dithranol; vitamin D analogs, including calcipotriol; and retinoids, non-biologics including methotrexate, ciclosporin, hydroxycarbamide, and fumarates including dimethyl fumarate; as well as one or more biologics, including antibodies or paratope-containing antibody portions to TNF-α, antibodies to pro-inflammatory cytokines interleukin-12, interleukin-23 and interleukin-17, and TNF inhibitors. Treatment of other epithelial tissue, such as the lining of the gut, is also disclosed.

1 . A method of for the treatment of a hyperproliferative disorder of epithelial tissue that comprises topically administering to a mammal in need a therapeutically effective amount of a halogenated xanthene hydrophilic pharmaceutical composition, in combination with a therapeutically effective amount of a targeted systemic anti-inflammatory agent. 
     
     
         2 . The method according to  claim 1 , wherein said topical halogenated xanthene hydrophilic pharmaceutical composition comprises a compound of Formula I or a pharmaceutically acceptable salt thereof as the active agent dissolved or dispersed in a hydrophilic vehicle in which 
       
         
           
           
               
               
           
         
         R 1  is independently F, Cl, Br, I, H or C 1 -C 4  alkyl; 
         R 2 , R 3 , R 4 , and R 5  are independently Cl, H or I with at least one substituent selected from R 2 , R 3 , R 4 , R 5  being I and at least one being Cl or H; 
         and R 6  is independently H or C 1 -C 4  alkyl; 
         R 11  is H or C 1 -C 4  alkyl; and 
         R 12  is H or C 1 -C 7  acyl. 
       
     
     
         3 . The method according to  claim 1 , wherein said topical halogenated xanthene pharmaceutical composition contains the halogenated xanthene or pharmaceutically acceptable salt thereof at a concentration of about 0.0001% to about 0.01% by weight. 
     
     
         4 . The method according to  claim 3 , wherein said topical halogenated xanthene pharmaceutical composition contains a viscosity builder that is present in an amount to provide a viscosity of the composition of about 10 to about 1000 centipoise (cps) at a temperature of 25° C. and one atmosphere. 
     
     
         5 . The method according to  claim 4 , wherein said topical halogenated xanthene pharmaceutical composition contains a water-soluble electrolyte present at a concentration of about 0.1 to about 2% by weight, or alternately, at a level sufficient to provide an osmolality of greater than approximately 100 mOsm/kg to about 600 mOsm. 
     
     
         6 . The method according to  claim 1 , wherein said targeted systemic anti-inflammatory agent is a small molecule or proteinaceous active agent other than an NSAID that is a COX-1 and/or COX-2 inhibitor. 
     
     
         7 . The method according to  claim 1 , wherein said targeted systemic anti-inflammatory agent is one or more of an inhibitor of TNF-alpha, an IL-17A, a mixed IL-12/IL-23 inhibitor, an IL-6 inhibitor, and a phosphodiesterase-4 inhibitor. 
     
     
         8 . The method according to  claim 7 , wherein said an inhibitor of TNF-alpha is one or more of adalimunab, certolizumab pegol, etanercept, golimumab, guselkumab and infliximab. 
     
     
         9 . The method according to  claim 7 , wherein said an inhibitor of IL-17A is one or more of ixekizumab, brodalumab or secukinumab. 
     
     
         10 . The method according to  claim 7 , wherein said an inhibitor of IL-12/IL-23 is one or more of ustekinumab or risankizumab. 
     
     
         11 . The method according to  claim 7 , wherein said an inhibitor of IL-6 is sarilumab. 
     
     
         12 . The method according to  claim 7 , wherein said inhibitor phosphodiesterase-4 is one or more of isapremilast or crisaborole. 
     
     
         13 . The method according to  claim 1 , wherein said targeted systemic anti-inflammatory agent is an immune system downregulating agent that is one or more of methotrexate, cyclosporine, and azathioprine. 
     
     
         14 . The method according to  claim 1 , wherein said targeted systemic anti-inflammatory agent is initially administered at the maximum tolerated dose. 
     
     
         15 . The method according to  claim 1 , wherein said epithelial tissue is skin.