Novel compositions comprising trimetrexate and methods of their synthesis and use

Abstract

This invention is directed to the novel composition of matter trimetrexate ascorbate, to compositions comprising trimetrexate ascorbate, and to compositions comprising trimetrexate and ascorbic acid. These compositions are useful in the treatment of diseases in mammals such as, but not limited to, cancer, bacterial and protozoal infections, malaria, psoriasis, and rheumatoid arthritis. The invention is further related to methods of stabilizing trimetrexate to degradation caused by heat, light, oxygen, or water.

What is claimed is:  
     
         1 . Trimetrexate ascorbate.  
     
     
         2 . The trimetrexate ascorbate of  claim 1  wherein said trimetrexate ascorbate is crystalline.  
     
     
         3 . The trimetrexate ascorbate of  claim 1  wherein said trimetrexate ascorbate is amorphous.  
     
     
         4 . A composition comprising trimetrexate ascorbate.  
     
     
         5 . The composition of  claim 4  wherein said composition is solid.  
     
     
         6 . The composition of  claim 4  wherein said composition is liquid.  
     
     
         7 . The composition of  claim 4  which further comprises an antioxidant.  
     
     
         8 . The composition of  claim 7  wherein the antioxidant is selected from group consisting of: acetone sodium bisulfite; bisulfite sodium; butylated hydroxy anisole; butylated hydroxy toluene; cystein; cysteinate HCl; dithionite sodium; gentisic acid; gentisic acid ethanolamine; glutamate monosodium; formaldehyde sulfoxylate sodium; metabisulfite potassium; metabisulfite sodium; monothioglycerol; propyl gallate; sulfite sodium; thioglycolate sodium and ascorbic acid.  
     
     
         9 . The composition of  claim 8  wherein said composition is solid and the antioxidant is monothioglycerol.  
     
     
         10 . The composition of  claim 9  wherein said composition is solid and the amount of monothioglycerol is from about 5 to about 25 weight percent.  
     
     
         11 . The composition of  claim 10  wherein the amount of monothioglycerol is from about 7.5 to about 20 weight percent.  
     
     
         12 . The composition of  claim 11  wherein the amount of monothioglycerol is from about 10 to about 15 weight percent.  
     
     
         13 . The composition of  claim 8  wherein said composition is liquid and the antioxidant is monothioglycerol.  
     
     
         14 . The composition of  claim 13  wherein the concentration of monothioglycerol is from about 1 to about 20 mg/ml.  
     
     
         15 . The composition of  claim 14  wherein the concentration of monothioglycerol is from about 2 to about 15 mg/ml.  
     
     
         16 . The composition of  claim 15  wherein the concentration of monothioglycerol is from about 3 to about 10 mg/ml.  
     
     
         17 . The composition of  claim 16  wherein the concentration of monothioglycerol is from about 4 to about 9 mg/ml.  
     
     
         18 . The composition of  claim 17  wherein the concentration of monothioglycerol is about 5 mg/ml.  
     
     
         19 . The composition of  claim 4  wherein said composition is a pharmaceutical composition.  
     
     
         20 . The composition of  claim 19  wherein said composition is sterile.  
     
     
         21 . The composition of  claim 19  which further comprises a pharmaceutically acceptable carrier.  
     
     
         22 . The composition of  claim 21  wherein the pharmaceutically acceptable carrier is an excipient selected from the group consisting of: sodium chloride; citric acid; tartaric acid; gelatin; carbohydrates such as dextrose, sucrose, sorbitol, inositol, dextran, and mannitol; EDTA; DTPA; and mixtures thereof.  
     
     
         23 . The composition of  claim 4  which further comprises a source of reduced folate.  
     
     
         24 . The composition of  claim 23  wherein the source of reduced folate is leucovorin.  
     
     
         25 . A composition comprising trimetrexate and ascorbic acid.  
     
     
         26 . The composition of  claim 25  wherein said composition is thermally stable.  
     
     
         27 . The composition of  claim 25  wherein said composition is light stable.  
     
     
         28 . The composition of  claim 25  wherein the molar ratio of trimetrexate to ascorbic acid is from about 1:0.1 to about 1:10.  
     
     
         29 . The composition of  claim 28  wherein the molar ratio of trimetrexate to ascorbic acid is from about 1:1 to about 1:5.  
     
     
         30 . The composition of  claim 29  wherein the molar ratio of trimetrexate to ascorbic acid is from about 1:2 to about 1:4.  
     
     
         31 . The composition of  claim 25  wherein said composition is solid.  
     
     
         32 . The composition of  claim 25  wherein said composition is liquid.  
     
     
         33 . The composition of  claim 32  which comprises trimetrexate in a concentration of from about 6 to about 18 mg/ml.  
     
     
         34 . The composition of  claim 33  which comprises trimetrexate in a concentration of from about 7 to about 15 mg/ml.  
     
     
         35 . The composition of  claim 34  which comprises trimetrexate in a concentration of from about 8 to about 14 mg/ml.  
     
     
         36 . The composition of  claim 35  which comprises trimetrexate in a concentration of from about 9 to about 13 mg/ml.  
     
     
         37 . The composition of  claim 36  which comprises trimetrexate in a concentration of about 10 mg/ml.  
     
     
         38 . The composition of  claim 32  which comprises ascorbic acid in a concentration of from about 5 to about 50 mg/ml.  
     
     
         39 . The composition of  claim 38  which comprises ascorbic acid in a concentration of from about 10 to about 40 mg/ml.  
     
     
         40 . The composition of  claim 39  which comprises ascorbic acid in a concentration of from about 15 to about 30 mg/ml.  
     
     
         41 . The composition of  claim 40  which comprises ascorbic acid in a concentration of from about 20 to about 25 mg/ml.  
     
     
         42 . The composition of  claim 25  which further comprises an antioxidant.  
     
     
         43 . The composition of  claim 42  wherein the antioxidant is selected from group consisting of: acetone sodium bisulfite; bisulfite sodium; butylated hydroxy anisole; butylated hydroxy toluene; cystein; cysteinate HCl; dithionite sodium; gentisic acid; gentisic acid ethanolamine; glutamate monosodium; formaldehyde sulfoxylate sodium; metabisulfite potassium; metabisulfite sodium; monothioglycerol; propyl gallate; sulfite sodium; thioglycolate sodium and ascorbic acid.  
     
     
         44 . The composition of  claim 43  wherein said composition is solid and the antioxidant is monothioglycerol.  
     
     
         45 . The composition of  claim 44  wherein the amount of monothioglycerol is from about 5 to about 25 weight percent.  
     
     
         46 . The composition of  claim 45  wherein the amount of monothioglycerol is from about 7.5 to about 20 weight percent.  
     
     
         47 . The composition of  claim 46  wherein the amount of monothioglycerol is from about 10 to about 15 weight percent.  
     
     
         48 . The composition of  claim 43  wherein said composition is liquid and the antioxidant is monothioglycerol.  
     
     
         49 . The composition of  claim 48  wherein the concentration of monothioglycerol is from about 1 to about 20 mg/ml.  
     
     
         50 . The composition of  claim 49  wherein the concentration of monothioglycerol is from about 2 to about 15 mg/ml.  
     
     
         51 . The composition of  claim 50  wherein the concentration of monothioglycerol is from about 3 to about 10 mg/ml.  
     
     
         52 . The composition of  claim 51  wherein the concentration of monothioglycerol is from about 4 to about 9 mg/ml.  
     
     
         53 . The composition of  claim 52  wherein the concentration of monothioglycerol is about 5 mg/ml.  
     
     
         54 . The composition of  claim 25  wherein said composition is a pharmaceutical composition.  
     
     
         55 . The composition of  claim 54  wherein said composition is sterile.  
     
     
         56 . The composition of  claim 54  which further comprises a pharmaceutically acceptable carrier.  
     
     
         57 . The composition of  claim 56  wherein the pharmaceutically acceptable carrier is an excipient selected from the group consisting of: sodium chloride; citric acid; tartaric acid; gelatin; carbohydrates such as dextrose, sucrose, sorbitol, inositol, dextran, and mannitol; EDTA; DTPA; and mixtures thereof.  
     
     
         58 . The composition of  claim 25  which further comprises a source of reduced folate.  
     
     
         59 . The composition of  claim 58  wherein the source of reduced folate is leucovorin.  
     
     
         60 . A liquid pharmaceutical composition comprising trimetrexate wherein said liquid pharmaceutical composition forms less than about 5 weight percent of impurities when sealed in a vial and maintained at a temperature of about 40° C. for about one month, said weight percent being based upon the weight of trimetrexate.  
     
     
         61 . A liquid pharmaceutical composition comprising trimetrexate wherein said liquid pharmaceutical composition forms less than about 2 weight percent of impurities when sealed in a vial and maintained at a temperature of about 25° C. for about six months, said weight percent being based upon the weight of trimetrexate.  
     
     
         62 . A liquid pharmaceutical composition comprising-trimetrexate wherein said liquid pharmaceutical composition forms less than about 2 weight percent of impurities when sealed in a vial and maintained at a temperature of about 5° C. for about one year, said weight percent being based upon (the weight of trimetrexate.  
     
     
         63 . The pharmaceutical composition of  claim 60 ,  61 , or  62  wherein said pharmaceutical composition is sterile.  
     
     
         64 . A dosage form of trimetrexate which comprises sterile trimetrexate ascorbate.  
     
     
         65 . A dosage form of trimetrexate which comprises sterile trimetrexate and sterile ascorbic acid.  
     
     
         66 . The dosage form of  claim 64  or  65  which further comprises leucovorin.  
     
     
         67 . A pharmaceutical composition of trimetrexate which is prepared from a solution comprising trimetrexate and ascorbic acid.  
     
     
         68 . The pharmaceutical composition of  claim 67  wherein the solution further comprises an antioxidant.  
     
     
         69 . A sterile lyophilized dosage form suitable for reconstitution and parenteral administration to a patient which comprises trimetrexate ascorbate.  
     
     
         70 . A sterile lyophilized dosage form suitable for reconstitution and parenteral administration to a patient which comprises trimetrexate and ascorbic acid.  
     
     
         71 . A pharmaceutical composition which comprises trimetrexate, ascorbic acid, and monothioglycerol.  
     
     
         72 . A method of treating a disease or condition associated with dihydrofolate reductase activity comprising administering to a subject in need of such treatment a therapeutically effective amount of trimetrexate ascorbate.  
     
     
         73 . A method of treating a disease or condition associated with dihydrofolate reductase activity comprising administering to a subject in need of such treatment a therapeutically effective amount of a composition comprising trimetrexate and ascorbic acid.  
     
     
         74 . The method of  claim 72  or  73  wherein the disease or condition associated with dihydrofolate reductase activity is a viral infection, fungal infection, yeast infection, bacteria infection, protozoa infection, psoriasis, rheumatoid arthritis, abnormal angiogenesis, or cancer.  
     
     
         75 . The method of  claim 74  wherein the bacteria infection is  Pneumocystis carinii  pneumonia, the protozoan infection is malaria, and the cancer is selected from the group consisting of: breast; colon; non-small cell lung, head and neck; colorectal; lung; prostate; ovary; renal; melanoma; gastrointestinal cancer; and osteogenic sarcoma.