Toll-like receptor agonist formulations and their use

Abstract

The present invention is directed generally to stable formulations of a TLR agonist preferably a TLR7 or a TLR8 agonist, for use in the treatment of cancer, preferably solid tumors and lymphomas. Specifically, the present invention is directed to stable formulations of up to 50 mg/ml of a TLR agonist which comprise a cyclodextrin.

1 . A solid or liquid formulation comprising a Toll-like receptor (TLR) agonist and a cyclodextrin, wherein said agonist is a benzo[b]azepine compound that is an agonist of TLR7, TLR8, or both. 
     
     
         2 . The formulation of  claim 1 , wherein the TLR agonist is selected from the group consisting of (1E, 4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and pharmaceutically acceptable salts thereof. 
     
     
         3 . The formulation of  claim 2 , wherein the TLR agonist is (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide, and pharmaceutically acceptable salts thereof. 
     
     
         4 . The formulation of  claim 1 , wherein the cyclodextrin is a β-cyclodextrin. 
     
     
         5 . The formulation of  claim 4 , wherein the β-cyclodextrin is sulfobutyl ether β-cyclodextrin. 
     
     
         6 . The formulation of  claim 4 , wherein the formulation comprises from about 1%-30% weight/volume of the β-cyclodextrin. 
     
     
         7 . The formulation of  claim 6 , wherein the formulation comprises from about 5%-15% weight/volume of the β-cyclodextrin. 
     
     
         8 . The formulation of  claim 1 , wherein the formulation is a liquid formulation and the TLR agonist is formulated at a concentration of from about 0.5 mg/ml to about 50 mg/ml. 
     
     
         9 . The formulation of  claim 8 , wherein the agonist is formulated at a concentration of from about 1 mg/ml to about 40 mg/ml. 
     
     
         10 . The formulation of  claim 9 , wherein the agonist is formulated at a concentration of from about 2 mg/ml to about 15 mg/ml. 
     
     
         11 . The formulation of  claim 1 , wherein the pH of the formulation is acidic. 
     
     
         12 . The formulation of  claim 11 , wherein the pH is about 6.5. 
     
     
         13 . The formulation of  claim 1 , wherein the formulation is a lyophilized formulation. 
     
     
         14 . A method for treating cancer in a subject comprising administering to the subject a TLR agonist formulation solubilized in a cyclodextrin, wherein the TLR agonist is selected from the group consisting of (1E, 4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-2-amino-N,N-bis(2-methoxyethyl)-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-N,N-diethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-8-(perfluoroethyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-N-ethyl-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-2-amino-8-(perfluoroethyl)-N-propyl-3H-benzo[b]azepine-4-carboxamide; (1E, 4E)-ethyl 2-amino-8-(pyrrolidine-1-carbonyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-ethyl 2-amino-8-(4-(methoxycarbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-ethyl 2-amino-8-(4-(methylcarbamoyl)phenyl)-3H-benzo[b]azepine-4-carboxylate; (1E, 4E)-2-amino-N,N-dipropyl-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxamide; and pharmaceutically acceptable salts thereof. 
     
     
         15 . The method of  claim 14 , wherein the TLR agonist is formulated at a concentration of at least 2 mg/ml. 
     
     
         16 . The method of  claim 14 , wherein the formulation is suitable for administration to the subject by injection. 
     
     
         17 . The method of  claim 14 , wherein the TLR agonist is administered to the subject at weekly or biweekly intervals. 
     
     
         18 . A method for treating an infectious disease in a subject comprising administering to the subject a TLR agonist formulation of  claim 1 . 
     
     
         19 . A method for treating atopic dermatitis in a subject comprising administering to the subject a TLR agonist formulation of  claim 1 . 
     
     
         20 . A pharmaceutical pack or kit comprising one or more containers filled with a liquid or lyophilized TLR agonist formulation, wherein the formulation comprises a cyclodextrin, and wherein the formulation contains at least 0.05 mg, 0.50 mg, 1.0 mg, 5.0 mg, 10 mg, 15 mg, 20 mg, 30 mg, or at least 50 mg TLR agonist. 
     
     
         21 . The method of  claim 14 , wherein the TLR agonist is administered at a daily dose of at least 0.05 mg, 0.50 mg, 1.0 mg, 5.0 mg, 10 mg, 15 mg, 20 mg, 30 mg, or at least 50 mg.