Bendamustine solid dispersions and continuous infusion

Abstract

Provided herein are pharmaceutical compositions comprising nitrogen mustard, for example bendamustine hydrochloride, solid dispersions substantially free of degradants. Also provided are methods of producing and administering nitrogen mustards and in particular bendamustine hydrochloride solid dispersions substantially free of degradants. The pharmaceutical compositions can be used for any disease that is sensitive to treatment with bendamustine hydrochloride, such as neoplastic diseases.

1 .- 94 . (canceled) 
     
     
         95 . A spray dried powder composition, comprising:
 a. a solid form of one or more excipients; and   b. a solid form of a bendamustine compound or pharmaceutically acceptable salt of a bendamustine compound selected from the group consisting of crystalline compound and amorphous compound, and combinations thereof uniformly and molecularly dispersed in excipient, wherein the bendamustine compound has less than 5% of a crystalline form that has peaks on an XRPD diffractogram at angles 8.3, 14, 16.8, 18.5±0.2 degrees 2θ, and less than 5% of a crystalline form that has peaks on an XRPD diffractogram at angles 7.9, 10.6, 15.5 and 19.7±0.2 degrees 2θ; wherein less than 0.5% of bendamustine dimer degradation product relative to the bendamustine compound, and wherein the bendamustine dimer degradation product is a compound of the following formula:   
       
         
           
           
               
               
           
         
       
     
     
         96 . The spray dried powder composition of  claim 95 , wherein the excipient can be dissolved in an aqueous phase and the composition comprises less than 0.5% of hydrolysis degradant HP1 relative to the bendamustine compound, wherein HP1 is a compound of the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         97 . The spray dried powder composition of  claim 95 , further comprising a saccharide excipient or a saccharide alcohol excipient selected from the group consisting of mannitol, maltitol, sorbitol, erythritol, xylitol, lactitol, lactose, sucrose, glycose, maltose, trehalose, dextrose, cyclodextrin, and combinations thereof. 
     
     
         98 . The spray dried powder composition of  claim 96 , further comprising a saccharide excipient or a saccharide alcohol excipient selected from the group consisting of mannitol, maltitol, sorbitol, erythritol, xylitol, lactitol, lactose, sucrose, glycose, maltose, trehalose, dextrose, cyclodextrin, and combinations thereof. 
     
     
         99 . The spray dried powder composition of  claim 95 , in the form of a solid dispersion, and further comprising a polymeric excipient selected from the group consisting of vinylpyrrolidone, ethylene glycol, propylene glycol, propylene carbonate, vinyl acetate, vinyl propionate, vinyl caprolactame, methyl methacrylate, methacrylic acid, polymers and co-polymers thereof, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), cellulose acetate, ethyl cellulose, or a mixture thereof. 
     
     
         100 . The spray dried powder composition of  claim 96 , in the form of a solid dispersion, and further comprising a polymeric excipient selected from the group consisting of vinylpyrrolidone, ethylene glycol, propylene glycol, propylene carbonate, vinyl acetate, vinyl propionate, vinyl caprolactame, methyl methacrylate, methacrylic acid, polymers and co-polymers thereof, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), cellulose acetate, ethyl cellulose, or a mixture thereof. 
     
     
         101 . An oral pharmaceutical dosage form comprising the spray dried powder composition of  claim 97 , wherein the amount of hydrolysis degradants are measured at the time of manufacturing release. 
     
     
         102 . An oral pharmaceutical dosage form comprising the spray dried powder composition of  claim 98 , wherein the amount of hydrolysis degradants are measured at the time of manufacturing release. 
     
     
         103 . An oral pharmaceutical dosage form comprising the spray dried powder composition of  claim 99 , wherein the amount of hydrolysis degradants are measured at the time of manufacturing release. 
     
     
         104 . An oral pharmaceutical dosage form comprising the spray dried powder composition of  claim 100 , wherein the amount of hydrolysis degradants are measured at the time of manufacturing release. 
     
     
         105 . A pharmaceutical dosage form comprising the composition of  claim 97 , wherein the amount of hydrolysis degradant HP1 is measured at the time of manufacturing release and wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes. 
     
     
         106 . A pharmaceutical dosage form comprising the composition of  claim 98 , wherein the amount of hydrolysis degradant HP1 is measured at the time of manufacturing release and wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes. 
     
     
         107 . A pharmaceutical dosage form comprising the composition of  claim 99 , wherein the amount of hydrolysis degradant HP1 is measured at the time of manufacturing release and wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes. 
     
     
         108 . A pharmaceutical dosage form comprising the composition of  claim 100 , wherein the amount of hydrolysis degradant HP1 is measured at the time of manufacturing release and wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes.