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 method of preparing a nitrogen mustard dry powder preparation, the method comprising:
 providing a nitrogen mustard compound or a pharmaceutically acceptable salt of the nitrogen mustard compound;   dissolving a polymeric excipient and the nitrogen mustard compound or the pharmaceutically acceptable salt of the nitrogen mustard compound in a non-aqueous solution at about 1% to about 100% (v/v) to form a pre-drying solution; or   dissolving the nitrogen mustard compound or the pharmaceutically acceptable salt of the nitrogen mustard compound in an aqueous solution to form a pre-drying solution, wherein the aqueous solution comprises a pH modifier or an agent providing chloride ions that minimizes the creation of hydrolysis degradants; and   spray-drying the pre-drying solution.   
     
     
         96 . The method of  claim 95 , wherein the spray-drying step comprises:
 continuously feeding the pre-drying solution into a spray-drying chamber through one or more atomizer nozzle; and   continuously blowing air or inert gas or a combination thereof, with or without the application of vacuum into the spray-drying chamber.   
     
     
         97 . The method of  claim 95 , wherein the nitrogen mustard compound is selected from the group consisting of bendamustine, cyclophosphamide, bisulfan, chlorambucil, carmustin, melphalan, uramustine, ifosfamide, mechlorethamine, lumustine, and combinations thereof. 
     
     
         98 . The method of  claim 95 , 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, and methacrylic acid. 
     
     
         99 . The method of  claim 95 , wherein the pH modifier is selected from the group consisting of trifluoroacetic acid, fluoroacetic acid, acetic acid, and citric acid. 
     
     
         100 . The method of  claim 95 , wherein the agent providing chloride ions is selected from the group consisting of potassium chloride, sodium chloride, and calcium chloride. 
     
     
         101 . The method of  claim 95 , wherein the non-aqueous solution comprises an organic solvent. 
     
     
         102 . The method of  claim 101 , wherein the organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide (DMSO), dimethyl acetamide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), tertbutylmethylether, ethyl ether, ethyl formate, isopropyl acetate, toluene, propyl acetate, and mixtures thereof. 
     
     
         103 . A nitrogen mustard dry powder preparation formed according to the method of  claim 95 . 
     
     
         104 . An oral pharmaceutical dosage form comprising the nitrogen mustard dry powder preparation of  claim 103 . 
     
     
         105 . A pharmaceutical dosage form comprising the nitrogen mustard dry powder preparation of  claim 103 , wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes. 
     
     
         106 . A method of preparing a nitrogen mustard dry powder preparation, the method comprising:
 combining, in a continuous mode of operation, a non-aqueous solution comprising a nitrogen mustard compound or a pharmaceutically acceptable salt of the nitrogen mustard compound and a water miscible organic solvent or a water immiscible organic solvent or a partially water miscible organic solvent at a combined concentration above its saturation point with water, with an aqueous solution comprising one or more pharmaceutically acceptable excipients to form a pre-drying solution; and   spray-drying the pre-drying solution.   
     
     
         107 . The method of  claim 106 , wherein the spray-drying step comprises:
 continuously feeding the pre-drying solution into a spray-drying chamber through one or more atomizer nozzle; and   continuously blowing air or inert gas or a combination thereof, with or without the application of vacuum into the spray-drying chamber.   
     
     
         108 . The method of  claim 106 , wherein the nitrogen mustard compound is selected from the group consisting of bendamustine, cyclophosphamide, bisulfan, chlorambucil, carmustin, melphalan, uramustine, ifosfamide, mechlorethamine, lumustine, and combinations thereof. 
     
     
         109 . The method of  claim 106 , wherein the water miscible organic solvent is selected from the group consisting of methanol, ethanol, n-propanol, iso-propanol, n-butanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl sulfoxide, dimethyl acetamide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, n-methyl-2-pyrrolidone (NMP), dimethylformamide (DMF), and mixtures thereof. 
     
     
         110 . The method of  claim 106 , wherein the partially water miscible organic solvent is selected from the group consisting of tertbutylmethylether, ethyl ether, ethyl formate, isopropyl acetate, toluene, methyl ethyl ketone, and propyl acetate. 
     
     
         111 . The method of  claim 106 , wherein the water immiscible organic solvent is selected from the group consisting of perfluorohexane, perfluorooctane, perflenapent, hexafluorobenzene, and perfluoromethylcyclohexane. 
     
     
         112 . A nitrogen mustard dry powder preparation formed according to the method of  claim 106 . 
     
     
         113 . An oral pharmaceutical dosage form comprising the nitrogen mustard dry powder preparation of  claim 112 . 
     
     
         114 . A pharmaceutical dosage form comprising the nitrogen mustard dry powder preparation of  claim 112 , wherein the pharmaceutical dosage form can be reconstituted into a pharmaceutically acceptable injectable form within 5 minutes.