Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same

Abstract

The present invention is directed to pharmaceutical compositions comprising melphalan and a cyclodextrin derivative, and methods of making and using the same.

What is claimed is: 
     
         1 . A method of treating a subject suffering from a neoplastic disorder, the method comprising:
 diluting a composition with an aqueous diluent to provide a dilute pharmaceutical composition comprising 25 mg to 125 mg of melphalan and a cyclodextrin derivative of formula 1:   
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 1 -(alkylene)-SO 3 — group, or an optionally substituted straight-chain or branched C 1 -C 6  group; 
         wherein at least one of R 1 , R 2 , P 3 , P 4 , R 5 , R 6 , R 7 , K 8  and R 9  is a straight-chain or branched C 1 -C 8 -(alkylene)-SO 3  group; 
         wherein the dilute pharmaceutical composition has, a pH of about 4 to about 6; 
         wherein the cyclodextrin derivative is present in a concentration of at least 50:1 (w/w) relative to: the melphalan, 
         wherein the melphalan in the dilute, pharmaceutical composition degrades by 2% or less at about 25Q C. within 0.5 hours after the diluting; and administering the dilute pharmaceutical composition, by injection to the subject in need thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the neoplastic disorder is selected from: myeloma, Multiple myeloma, melanoma, acute myelogenous leukemia, malignant melanoma, breast cancer, ovarian cancer, testicular cancer, advanced prostate cancer, a neuroendocrine cancer, metastatic melanoma, a metastatic neuroendocrine tumor, a metastatic adenocarcinoma tumor, hepatocellular carcinoma, osteogenic sarcoma, polycythemia veraplasma; plasma cell neoplasm, amyloidosis, scleromyxedema, and combinations thereof. 
     
     
         3 . The method of  claim 2 , wherein the neoplastic disorder is multiple myeloma and the administering is systemic and provides, palliative treatment of the multiple myeloma. 
     
     
         4 . The method of  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9 . is a hydroxy-substituted-C 3  group. 
     
     
         5 . The method of  claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently a straight-chain or branched C 1 -C 8 -(alkylene)-SO 3 — group having a degree of substitution of 4 to 8 per cyclodextrin derivative, and the remaining substituents are —H. 
     
     
         6 . The method of  claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is substituted with a straight-chain C 4 -(alkylene)-SO 3 — group. 
     
     
         7 . The method of  claim 1 , wherein the cyclodextrin derivative is a compound of formula IL 
       
         
           
           
               
               
           
         
         wherein R═(H) 21-x , or ((CH 2 ) 4 SO 3 Na + ) x  and x=6.0-7.1; 
         wherein the pharmaceutical composition comprises about 50 mg of melphalan as a hydrochloride salt; and 
         wherein the cyclodextrin derivative is: present in a concentration, of 50:1 to 100:1 (w/w) relative to the melphalan. 
       
     
     
         8 . The method of  claim 1 , wherein, the dilute pharmaceutical composition is substantially free of an alcohol. 
     
     
         9 . The method of  claim 1 , wherein the aqueous diluent is a saline solution. 
     
     
         10 . The method of  claim 1 , wherein the, subject suffering from the neoplastic disorder is pediatric subject. 
     
     
         11 . The method of  claim 1 , wherein the melphalan in the dilute pharmaceutical composition degrades by 4% or less at 25° C. within 10 hours after the diluting: 
     
     
         12 . The method of  claim 1 , wherein the dilute pharmaceutical composition is stored about 0.5 hours to about 18 hours prior to the administering. 
     
     
         13 . The method of  claim 1 , wherein the administering, provides a melphalan C max  in the subject suffering from a neoplastic disorder that is at least 20% or greater than a melphalan C max  provided by a melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative. 
     
     
         14 . The method of  claim 1 , wherein the administering provides a melphalan AUC 0-t  in the subject suffering from a neoplastic disorder that is at least 20% or greater than a melphalan AUC 0-t  provided by a melphalan formulation containing an: equivalent dose of melphalan and lacking the cyclodextrin derivative. 
     
     
         15 . A method for conditioning a subject for whom a stem cell transplantation has been indicated, the method comprising:
 administering a melphalan dose of 50 mg/m 2  to 300 mg/m 2  per day to the subject for whom a stem cell transplantation has been indicated, wherein the melphalan dose is administered in a pharmaceutical: composition comprising melphalan and a cyclodextrin derivative of formula I:   
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 8 -(alkylene)-SO 3 — group, or an optionally substituted straight-chain or branched C 1 -C 6  group; 
         wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a straight-chain or branched C1-C8-(alkylene)-SO 3  group; 
         wherein the pharmaceutical composition has a pH of about 4 to about 6; and 
         wherein the cyclodextrin derivative is present in a ratio of at least 25:1 (w/w) relative to the melphalan. 
       
     
     
         16 . The method of  claim 15 , wherein the administering is for a period of two or more days. 
     
     
         17 . The method of  claim 15 , wherein, the subject in need of the stem cell transplantation is a pediatric subject. 
     
     
         18 . The method of  claim 15 , wherein the administering is performed intravenously. 
     
     
         19 . The method of  claim 15 , wherein, the administering is performed via a limb perfusion. 
     
     
         20 . The method of  claim 15 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a hydroxy-substituted-C 3  group. 
     
     
         21 . The method of  claim 15 , wherein the cyclodextrin derivative is a compound of formula II: 
       
         
           
           
               
               
           
         
         wherein R═(H) 21-x  or (—(CH 2 ) 4 —SO 3 —Na + ) x , and x=6.0-7.1; 
         wherein the pharmaceutical composition comprises about 200 mg of melphalan as a hydrochloride salt; and 
         wherein the cyclodextrin derivative is present in a ratio of 25:1. to 35:1 (w/w) relative to the: melphalan. 
       
     
     
         22 . The method of  claim 15 , wherein the subject for whom. A stem cell transplantation has: been indicated suffers from a disease or disorder selected from: myeloma, multiple myeloma, a lymphoma, non-Hodgkin lymphoma, leukemia, acute myeloid leukemia, Hodgkin's disease, acute lymphoblastic leukemia, a: myelodysplastic syndrome, a myeloproliferative disorder; chronic myelogenous leukemia, neuroblastoma, aplastic anemia, chronic granulocytic leukemia, a neuroblastoma, sickle-cell disease, osteogenic sarcoma, Ewing's sarcoma, a desmoplastic small round cell tumor, plasma cell neoplasm, amyloidosis, scleromyxedema, and combinations thereof. 
     
     
         23 . The method of  claim 15 , comprising diluting a concentrated melphalan composition with an aqueous diluent to provide the pharmaceutical composition, 
     
     
         24 . The method of  claim 23 , wherein the concentrated melphalan composition comprises 50 mg to 500 mg of melphalan. 
     
     
         25 . The method of  claim 23 , wherein the concentrated melphalan composition comprises about 200 mg. 
     
     
         26 . The method of  claim 15 , wherein the pharmaceutical composition is substantially free of an alcohol. 
     
     
         27 . The method of  claim 23 , wherein the aqueous diluent is a saline solution. 
     
     
         28 . The method of  claim 23 , wherein the melphalan in the pharmaceutical composition degrades by 4% or less at about 25° C. within 10 hours after the diluting. 
     
     
         29 . The method of  claim 23 , wherein the pharmaceutical composition is stored about 0.5 hours to about 12 hours prior to the administering. 
     
     
         30 . The method of  claim 15 , wherein the administering provides a melphalan C max  in the subject for whom a stem cell transplantation has been indicated that is at least 20% or greater than a melphalan C max  provided by a melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative. 
     
     
         31 . The method of  claim 15 , wherein the administering provides a melphalan AUC 0-t  in the subject for whom a stem cell transplantation has: been indicated that is at least 20% or greater than a melphalan. AUC 0-t  provided by a. melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative. 
     
     
         32 . A pharmaceutical composition comprising:
 25 mg to 125 mg of melphalan as a hydrochloride salt;   an optional buffer; and   a cyclodextrin derivative of formula 1:   
       
         
           
           
               
               
           
         
         wherein n s 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 8 -(alkylene)-SO 3   −  group, or an optionally substituted straight-chain or branched C 1 -C 6  group; 
         wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is a, straight-chain or branched C 1 -C 8 -(alkylene)-SO 3   −  group; 
         wherein the pharmaceutical composition has a pH of about 4 to about 6, wherein dilution of the pharmaceutical composition with an aqueous solution provides a dilute pharmaceutical composition in which the melphalan degrades by 2% or less at about 25° C. within 5 hours after the dilution; and 
         wherein the cyclodextrin derivative is present in a ratio of 50:1 to 100:1 (w/w) relative to the melphalan. 
       
     
     
         33 . The pharmaceutical composition of  claim 32 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a hydroxy-substituted-C 3  group. 
     
     
         34 . The pharmaceutical composition of  claim 32 , wherein the cyclodextrin derivative is a compound of formula: II: 
       
         
           
           
               
               
           
         
         wherein R═(H) 21-x  or (—(CH 2 ) 4 SO 3 Na + ) x , and x=6.0-7.1; 
         wherein the pharmaceutical composition comprises about 50 mg of melphalan as a hydrochloride salt; and 
         wherein the cyclodextrin derivative, is present in a ratio, of about 55:1 (w/w) relative to the melphalan. 
       
     
     
         35 . A pharmaceutical composition comprising;
 150 mg to 250 mg of melphalan as a hydrochloride salt;   an optional buffer; and   a cyclodextrin derivative of formula I:   
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 8 (alkylene)-SO 3 — group, or an optionally substituted straight-chain or branched C 1 -C 6  group; 
         wherein at least one of R1, R2, R3, R4, R5, R6, R7, R8 and R9 is a straight-chain or branched C 1 -C 8 (alkylene)-S0 3   −  group; 
         wherein the pharmaceutical composition has a pH of about 4 to about 6, 
         wherein dilution of the pharmaceutical composition with an aqueous solution provides a melphalan solution in. which the melphalan degrades by 2% or loss a about 25° C. within 5 hours after the dilution; and 
         wherein the cyclodextrin derivative is present in a ratio of 25:1 to 35:1 (w/w) relative to the melphalan. 
       
     
     
         36 . The pharmaceutical composition of  claim 35 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a hydroxy-substituted C 3  group. 
     
     
         37 . The pharmaceutical composition of  claim 35 , wherein the cyclodextrin derivative is a compound of formula II: 
       
         
           
           
               
               
           
         
         wherein R═(H) 21-x  or (—(CH 2 ) 4 SO 3 Na + ) x , and x=6.0-7.1; 
         wherein the pharmaceutical composition comprises about 200 mg of melphalan as a hydrochloride salt; and 
         wherein the cyclodextrin derivative is present in a ratio of about 30:1 (w/w) relative to the melphalan. 
       
     
     
         38 . A pharmaceutical kit comprising:
 a first container comprising 25 mg to 125 mg of melphalan as a hydrochloride salt and an optional water-soluble polymer; and   a second container comprising an aqueous diluent, an optional buffer, and a cyclodextrin derivative of formula I:   
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 8 -(alkylene)-S0 3   −  group, or an optionally substituted straight-chain or branched C1-C6 group; 
         wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  is a straight-chain or branched C 1 -C 8 (alkylene)-S0 3   −  group; 
         wherein the cyclodextrin derivative is present in the second container in a concentration of at least 50:1 (w/w) relative to the melphalan; and 
         wherein combining the first container and. the second. container provides a dilute pharmaceutical composition having a pH of about 4 to about 6 that degrades by 2% or less at about 25° C. within 5 hours after the diluting. 
       
     
     
         39 . The pharmaceutical kit of  claim 38 , wherein the first container comprises povidone in an amount of 10 mg to 3.0 mg, and the second container comprises a pH-adjusting agent in a concentration sufficient to provide a pH of about 4 to about 6 when the first container and the second container are combined. 
     
     
         40 . A pharmaceutical kit comprising;
 a first container comprising 150 mg to 250 mg of melphalan as a hydrochloride salt and. an optional water-soluble polymer; and   a second container comprising an aqueous diluent, an optional buffer, and a cyclodextrin derivative of formula I:   
       
         
           
           
               
               
           
         
         wherein n is 4, 5 or 6; 
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are independently —H, a straight-chain or branched C 1 -C 8 (alkylene)-S0 3  group, or an optionally substituted straight-chain or branched C 1 -C 6  group; 
         wherein at least one of RI, R2, R3, R4, R5, R6, R7, R8 and R9 is a straight-chain or branched C 1 -C 8 (alkylene)-S0 3   −  group; 
         wherein the cyclodextrin derivative is present in the second container in a concentration of 25:1 to 35:1 (w/w) relative to the melphalan; and 
         wherein combining the first container and the second container provides a dilute pharmaceutical composition having a pH of about 4 to about 6 that degrades by 2% or less at about 25° C. within 5 hours after the diluting. 
       
     
     
         41 . The pharmaceutical kit of  claim 40 , wherein the first container comprises povidone in an amount of 10 mg to 30 mg, and the second container comprises a pH-adjusting agent in a concentration sufficient to provide a pH of about 4 to about 6 when the first container and the second container are combined. 
     
     
         42 . The pharmaceutical kits of  claim 40 , wherein the cyclodextrin derivative is a compound of formula II: 
       
         
           
           
               
               
           
         
         wherein R═(H) 21-x  or (—(CH 2 ) 4 SO 3   − Na + ) x , and x=6.0-7.1; 
         wherein the first container comprises about 200 mg of melphalan as a hydrochloride salt; and 
         wherein the cyclodextrin derivative is present, in the second container in an amount of about 30:1 (w/w) relative to the melphalan.