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, and wherein the spray-dried solid dispersion comprises less than 8% by weight water. 
     
     
         76 . The spray-dried solid dispersion of  claim 75 , wherein the excipient is a saccharide excipient or a saccharide alcohol excipient. 
     
     
         77 . The spray-dried solid dispersion of  claim 76 , 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. 
     
     
         78 . The spray-dried solid dispersion of  claim 76 , wherein the weight ratio of the nitrogen mustard compound to excipient is between about 5:1 to about 1:20. 
     
     
         79 . The spray-dried solid dispersion of  claim 75 , wherein the excipient is a polymer excipient. 
     
     
         80 . The spray-dried solid dispersion of  claim 79 , wherein the polymer excipient is dissolved in a non-aqueous solution, and wherein the polymer excipient is 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. 
     
     
         81 . The spray-dried solid dispersion of  claim 75 , comprising a non-aqueous solvent. 
     
     
         82 . The spray-dried solid dispersion of  claim 81 , wherein the non-aqueous solvent is selected from the group consisting of tert-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. 
     
     
         83 . The spray-dried solid dispersion of  claim 75  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. 
     
     
         84 . A pharmaceutical composition comprising the spray-dried solid dispersion of  claim 75 . 
     
     
         85 . The pharmaceutical composition of  claim 84 , wherein the morphology and physical characteristics of the spray-dried solid dispersion enable consistent powder flow. 
     
     
         86 . A pharmaceutical dosage form comprising the spray-dried solid dispersion of  claim 75  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. 
     
     
         87 . The pharmaceutical dosage form of  claim 86  that can be reconstituted into a pharmaceutically acceptable injectable form within 5, 4, 3, 2, or 1 minutes. 
     
     
         88 . An oral pharmaceutical dosage form comprising the spray-dried solid dispersion of  claim 75  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. 
     
     
         89 . 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. 
     
     
         90 . A method of treating a medical condition in a patient comprising dissolving the spray-dried solid dispersion of  claim 75  in a pharmaceutically acceptable solvent to produce a pharmaceutically acceptable solution; and administering to the patient a therapeutically effective amount of the pharmaceutically acceptable solution, wherein the medical condition is amenable to treatment with the pharmaceutically acceptable solution. 
     
     
         91 . The method of treating according to  claim 90 , wherein the medical condition is selected from the group consisting of chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease. 
     
     
         92 . The method of treating according to  claim 90 , wherein the medical condition is non-Hodgkin's lymphoma. 
     
     
         93 . The method of treating according to  claim 90 , wherein the medical condition is chronic lymphocytic leukemia. 
     
     
         94 . The method of treating according to  claim 90 , wherein the medical condition is multiple myeloma. 
     
     
         95 . The method of treating according to  claim 90 , wherein the pharmaceutically acceptable solution is administered in combination with one or more antineoplastic agents. 
     
     
         96 . The method of treating according to  claim 95 , wherein the one or more antineoplastic agents is an antibody specific for CD20. 
     
     
         97 . A method of treating a medical condition in a patient comprising using the spray-dried solid dispersion of  claim 75  to obtain a pharmaceutically acceptable oral solid dosage form; and administering to the patient a therapeutically effective amount of the pharmaceutically acceptable oral solid dosage form, wherein the medical condition is amenable to treatment with the pharmaceutically acceptable oral solid dosage form. 
     
     
         98 . The method of treating according to  claim 97 , wherein the medical condition is selected from the group consisting of chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, small cell lung cancer, and an autoimmune disease. 
     
     
         99 . The method of treating according to  claim 97 , wherein the medical condition is non-Hodgkin's lymphoma. 
     
     
         100 . The method of treating according to  claim 97 , wherein the medical condition is chronic lymphocytic leukemia. 
     
     
         101 . The method of treating according to  claim 97 , wherein the medical condition is multiple myeloma. 
     
     
         102 . The method of treating according to  claim 97 , wherein the pharmaceutically acceptable oral solid dosage form is administered in combination with one or more antineoplastic agents. 
     
     
         103 . The method of treating according to  claim 102 , wherein the one or more antineoplastic agents is an antibody specific for CD20.