Liposomal corticosteroids for treatment of inflammatory disorders in humans

Abstract

The invention relates to a pharmaceutical composition comprising liposomes composed of non-charged vesicle-forming lipids, optionally including not more than 10 mole percent of negatively charged vesicle-forming lipids and/or not more than 10 mole percent of PEGylated lipids, the liposomes having a selected mean particle diameter in the size range of 40-200 nm and comprising a first corticosteroid in water soluble form, for the site-specific treatment of inflammatory disorders in humans, providing in human patients a fast, strong, and durable anti-inflammatory effect for at least 2 weeks at a dose of at most 5 mg/kg body weight of prednisolone or an equipotent dose corticosteroid other than prednisolone at a treatment frequency of at most once per two weeks. Furthermore the present invention relates to the application of the above-mentioned pharmaceutical composition given as intervention therapy in inflammatory disorders such as rheumatic disease or a related inflammatory connective tissue disorder, inflammatory diseases of the kidney or inflammatory bowel disorders, in combination with chronic therapy with a second free corticosteroid formulation or in combination with chronic treatment with a disease-modifying agent such as methotrexate.

1 .- 19 . (canceled) 
     
     
         20 . A method for treating an inflammatory disorder, comprising intravenously administering to a human in need thereof liposomes comprising prednisolone, and having a mean particle diameter ranging from 40-200 nm, the liposomes having a composition comprising:
 (i) 0-50 mol % of cholesterol,   (ii) 50-90 mol % of non-charged vesicle-forming lipids comprising saturated alkyl chains,   (iii) 0-10 mol % of amphipathic vesicle-forming lipids coupled to polyethylene glycol, and   (iv) 1-10 mol % of a negatively charged vesicle-forming lipid;   wherein the prednisolone is administered at a dose of at most 5 mg/kg body weight, and;   wherein the liposomes are administered at most once per two weeks.   
     
     
         21 . The method according to  claim 20 , further comprising administering a second, free corticosteroid at most once per two weeks. 
     
     
         22 . The method according to  claim 20 , wherein the method further comprises administering an agent selected from the group consisting of methotrexate, hydroxychloroquine, leflunomide, cyclophosphamide, 5-fluorouracil, a 5-ASA agent, 6-mercaptopurine, mycophenolate mofetil, or azathioprine. 
     
     
         23 . The method according to  claim 22 , wherein the human is administered a single treatment with the liposomes following a flare of the inflammatory disorder. 
     
     
         24 . The method according to  claim 22 , wherein the agent is administered as part of maintenance therapy for the inflammatory disorder. 
     
     
         25 . The method according to  claim 20 , wherein the liposomes comprise 2.5 to 10 mol % of negatively charged vesicle-forming lipids and/or 2.5 to 10 mol % of PEGylated lipids. 
     
     
         26 . The method according to  claim 20 , further comprising administering an additional corticosteroid selected from the group consisting of dexamethasone and methylprednisolone. 
     
     
         27 . The method according to  claim 20 , further comprising administering an additional corticosteroid selected from the group consisting of budesonide, flunisolide and fluticasone propionate. 
     
     
         28 . The method according to  claim 20 , wherein the prednisolone is administered at a dose of at most 3 mg/kg body weight. 
     
     
         29 . The method according to  claim 20 , wherein the prednisolone is administered at a dose of at most 2 mg/kg body weight. 
     
     
         30 . A method for treating inflammatory disorder colitis ulcerosa and/or Crohn's disease, comprising intravenously administering to a human in need thereof liposomes comprising prednisolone, and having a mean particle diameter ranging from 40-200 nm, the liposomes having a composition comprising:
 (i) 0-50 mol % of cholesterol,   (ii) 50-90 mol % of non-charged vesicle-forming lipids comprising saturated alkyl chains,   (iii) 0-10 mol % of amphipathic vesicle-forming lipids coupled to polyethylene glycol, and   (iv) 1-10 mol % of a negatively charged vesicle-forming lipid;   wherein the prednisolone is administered at a dose of at most 5 mg/kg body weight, and;   wherein the liposomes are administered at most once per two weeks.   
     
     
         31 . The method according to  claim 30 , further comprising administering a second, free corticosteroid at most once per two weeks. 
     
     
         32 . The method according to  claim 30 , wherein the method further comprises administering an agent selected from the group consisting of methotrexate, hydroxychloroquine, leflunomide, cyclophosphamide, 5-fluorouracil, a 5-ASA agent, 6-mercaptopurine, mycophenolate mofetil, or azathioprine. 
     
     
         33 . The method according to  claim 32 , wherein the human is administered a single treatment with the liposomes following a flare of the inflammatory disorder. 
     
     
         34 . The method according to  claim 32 , wherein the agent is administered as part of maintenance therapy for the inflammatory disorder. 
     
     
         35 . The method according to  claim 30 , wherein the liposomes comprise 2.5 to 10 mol % of negatively charged vesicle-forming lipids and/or 2.5 to 10 mol % of PEGylated lipids. 
     
     
         36 . The method according to  claim 30 , further comprising administering an additional corticosteroid selected from the group consisting of dexamethasone and methylprednisolone. 
     
     
         37 . The method according to  claim 30 , further comprising administering an additional corticosteroid selected from the group consisting of budesonide, flunisolide and fluticasone propionate. 
     
     
         38 . The method according to  claim 30 , wherein the prednisolone is administered at a dose of at most 3 mg/kg body weight. 
     
     
         39 . The method according to  claim 30 , wherein the prednisolone is administered at a dose of at most 2 mg/kg body weight.