Bendamustine pharmaceutical compositions

Abstract

Provided herein are pharmaceutical formulations of dry-powder bendamustine suitable for pharmaceutical use. Also provided are methods of producing dry-powder bendamustine. The pharmaceutical formulations can be used for any disease that is sensitive to treatment with bendamustine, such as neoplastic diseases.

1 - 74 . (canceled) 
     
     
         75 . A spray-dried solid dispersion comprising a nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers, wherein the spray-dried solid dispersion is substantially free of hydrolysis degradants of the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, wherein the nitrogen mustard compound is selected from the group consisting of carmustine and mechlorethamine, and wherein the spray-dried solid dispersion is produced with a spray drier having an air flow temperature between about 40° C. to about 120° C. or an outlet spray chamber temperature between about 50° C. and about 120° C. 
     
     
         76 . A spray-dried solid dispersion comprising a nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, diluents, or carriers, wherein the nitrogen mustard compound is selected from the group consisting of carmustine and mechlorethamine, wherein the spray-dried solid dispersion is substantially free of hydrolysis degradants of the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, and wherein the spray-dried solid dispersion comprises less than 1% by weight water. 
     
     
         77 . The spray-dried solid dispersion of  claim 75  or  76 , wherein the excipient is a saccharide excipient or a saccharide alcohol excipient. 
     
     
         78 . The spray-dried solid dispersion of  claim 77 , wherein the saccharide excipient or saccharide alcohol excipient is selected from the group consisting of mannitol, maltitol, sorbitol, erythritol, xylitol, lactitol, lactose, sucrose, glucose, maltose, trehalose, dextrose, and combinations thereof. 
     
     
         79 . The spray-dried solid dispersion of  claim 77 , wherein the weight ratio of the nitrogen mustard compound to excipient is between about 5:1 to about 1:20. 
     
     
         80 . The spray-dried solid dispersion of  claim 75  or  76 , wherein the excipient is a polymer excipient. 
     
     
         81 . The spray-dried solid dispersion of  claim 80 , wherein the polymer excipient is dissolved in a non-aqueous solution selected from the group consisting of vinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate (HPMC-AS), ethylene glycol, propylene glycol, propylene carbonate, vinyl acetate, vinyl propionate, vinyl caprolactam, cellulose acetate, ethyl cellulose, methyl methacrylate, methacrylic acid and combinations thereof. 
     
     
         82 . The spray-dried solid dispersion of  claim 75  or  76 , comprising a non-aqueous solvent. 
     
     
         83 . The spray-dried solid dispersion of  claim 82 , wherein the non-aqueous solvent is selected from the group consisting of tent-butanol, n-propanol, n-butanol, isopropanol, ethanol, methanol, acetone, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, and mixtures thereof. 
     
     
         84 . The spray-dried solid dispersion of  claim 75  or  76  that comprises less than 0.5%, 0.4%, 0.3%, 0.2%, 0.15% or 0.1% of hydrolysis degradants of the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof. 
     
     
         85 . A pharmaceutical composition comprising the spray-dried solid dispersion of  claim 75  or  76 . 
     
     
         86 . The pharmaceutical composition of  claim 85 , wherein the morphology and physical characteristics of the spray-dried solid dispersion enable consistent powder flow. 
     
     
         87 . A pharmaceutical dosage form comprising the spray-dried solid dispersion of  claim 75  or  76  and not more than about 0.4%, 0.3%, 0.2%, 0.15% or 0.1% hydrolysis degradants relative to the amount of the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable container, wherein the amount of the hydrolysis degradant is present pre-reconstitution or at time zero after reconstitution of the dosage form. 
     
     
         88 . The pharmaceutical dosage form of  claim 87  that can be reconstituted into a pharmaceutically acceptable injectable form within 5, 4, 3, 2, or 1 minutes. 
     
     
         89 . An oral pharmaceutical dosage form comprising the spray-dried solid dispersion of  claim 75  or  76  and not more than about 0.4%, 0.3%, 0.2%, 0.15% or 0.1% of hydrolysis degradants relative to the amount of the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable closure, wherein the amount of hydrolysis degradant is present at the time of manufacturing release. 
     
     
         90 . The spray-dried solid dispersion of  claim 75  comprising the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, in combination with ibrutinib, or a pharmaceutically acceptable salt thereof. 
     
     
         91 . The spray-dried solid dispersion of  claim 76  comprising the nitrogen mustard compound, or a pharmaceutically acceptable salt thereof, in combination with ibrutinib, or a pharmaceutically acceptable salt thereof.