Rapidly infusing compositions with methotrexate and treatment methods

Abstract

A rapidly infusing composition that includes a pharmaceutically acceptable binder and/or excipient system containing gelatin and a sugar alcohol, and methotrexate. Also provided is a method of treating an autoimmune disease and/or inflammatory condition in a subject, whereby the subject in need thereof is administered, via the oral mucosa, the rapidly infusing composition. The autoimmune disease and/or inflammatory condition may include, inter alia, rheumatoid arthritis, dermatomyositis, psoriasis, systemic lupus erythematosus, eczema, vasculitis, psoriatic arthritis, type-Ii diabetes, multiple sclerosis, Crohn's disease, ulcerative colitis, and sarcoidosis, including refractory/diseases/conditions thereof.

1 . A rapidly infusing composition, comprising:
 a pharmaceutically acceptable binder and/or excipient system comprising gelatin and a sugar alcohol, and   methotrexate.   
     
     
         2 . The rapidly infusing composition of  claim 1 , which is lyophilized. 
     
     
         3 . The rapidly infusing composition of  claim 1 , which has a disintegration time of approximately 1 to 30 seconds in deionized water maintained at 37° C.±2° C. 
     
     
         4 . The rapidly infusing composition of  claim 1 , which has a disintegration time of approximately 1 to 5 seconds in deionized water maintained at 37° C.±2° C. 
     
     
         5 . The rapidly infusing composition of  claim 1 , wherein the gelatin is present in the rapidly infusing composition in an amount of 10 to 35 wt. %, based on a total weight of the rapidly infusing composition on a dry basis. 
     
     
         6 . The rapidly infusing composition of  claim 1 , wherein the gelatin is mammalian gelatin. 
     
     
         7 . The rapidly infusing composition of  claim 6 , wherein the mammalian gelatin is bovine gelatin. 
     
     
         8 . The rapidly infusing composition of  claim 1 , wherein the sugar alcohol is present in the rapidly infusing composition in an amount of 5 to 35 wt. %, based on a total weight of the rapidly infusing composition on a dry basis. 
     
     
         9 . The rapidly infusing composition of  claim 1 , wherein the sugar alcohol comprises mannitol. 
     
     
         10 . The rapidly infusing composition of  claim 1 , wherein the methotrexate is present in the rapidly infusing composition in an amount of 10 to 70 wt. %, based on a total weight of the rapidly infusing composition on a dry basis. 
     
     
         11 . The rapidly infusing composition of  claim 1 , wherein the rapidly infusing composition is formulated with a solid form of the methotrexate. 
     
     
         12 . The rapidly infusing composition of  claim 1 , wherein the rapidly infusing composition is formulated with a solid form of the methotrexate having a purity between 95 and 99.9 wt. %. 
     
     
         13 . The rapidly infusing composition of  claim 1 , wherein the rapidly infusing composition is formulated With a solid form of the methotrexate that has been micronized to have a D50 diameter between 1 and 50 μm. 
     
     
         14 . The rapidly infusing composition of  claim 1 , further comprising at least one selected from the group consisting of a sweetener, a flavorant, and a colorant. 
     
     
         15 . A process for manufacturing the rapidly infusing composition of  claim 1 , comprising:
 dissolving gelatin and the sugar alcohol in water to form a solution;   adding the methotrexate to the solution to form a drug product suspension; and   lyophilizing the drug product suspension to remove water and form the rapidly infusing composition.   
     
     
         16 . A method of treating an autoimmune disease and/or inflammatory condition in a subject, comprising:
 administering to the subject in need thereof, via the oral mucosa, a therapeutically effective amount of the rapidly infusing composition of  claim 1 .   
     
     
         17 . The method of  claim 16 , wherein the rapidly infusing composition is administered to the subject via the buccal mucosa. 
     
     
         18 . The method of  claim 16 , wherein the therapeutically effective amount of the rapidly infusing composition is that which provides from 1 to 100 mg of methotrexate per dose. 
     
     
         19 . The method of  claim 16 , wherein the rapidly infusing composition is administered to the subject 1 to 2 times per week. 
     
     
         20 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is a systemic autoimmune disease. 
     
     
         21 . The method of  claim 20 , wherein the systemic autoimmune disease is rheumatoid arthritis. 
     
     
         22 . The method of  claim 20 , wherein the systemic autoimmune disease is dermatomyositis. 
     
     
         23 . The method of  claim 20 , wherein the systemic autoimmune disease is psoriasis. 
     
     
         24 . The method of  claim 20 , wherein the systemic autoimmune disease is systemic lupus erythematosus. 
     
     
         25 . The method of  claim 20 , wherein the systemic autoimmune disease is eczema. 
     
     
         26 . The method of  claim 20 , wherein the systemic autoimmune disease is vasculitis. 
     
     
         27 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is an inflammatory joint condition. 
     
     
         28 . The method of  claim 27 , wherein the inflammatory joint condition is psoriatic arthritis. 
     
     
         29 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is an endocrine disease. 
     
     
         30 . The method of  claim 29 , wherein the endocrine disease is type-II diabetes. 
     
     
         31 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is a neuronal disease. 
     
     
         32 . The method of  claim 31 , wherein the neuronal disease is multiple sclerosis. 
     
     
         33 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is an inflammatory bowel disease. 
     
     
         34 . The method of  claim 33 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         35 . The method of  claim 33 , wherein the inflammatory bowel disease is ulcerative colitis. 
     
     
         36 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is sarcoidosis. 
     
     
         37 . The method of  claim 16 , wherein the autoimmune disease and/or inflammatory condition is a refractory autoimmune disease and/or inflammatory condition. 
     
     
         38 . The method of  claim 16 , wherein the rapidly infusing composition is administered to the subject in combination with a second therapeutic agent. 
     
     
         39 . The method of  claim 38 , wherein the second therapeutic agent is a disease modifying antirheumatic drug. 
     
     
         40 . The method of  claim 39 , wherein the disease modifying antirheumatic drug is a tumor necrosis factor (TNF) antagonist. 
     
     
         41 . The method of  claim 38 , wherein the second therapeutic drug is folic acid or derivative thereof.