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 . A spray dried or fluidized-bed spray dried solid dispersion composition comprising
 a. a solid form of one or more excipients;   b. a solid form of a nitrogen mustard compound selected from the group consisting of crystalline nitrogen mustard compound and amorphous nitrogen mustard compound, and combinations thereof; and   c. less than 0.2% of hydrolysis degradation products relative to the nitrogen mustard compound.   
     
     
         2 - 87 . (canceled) 
     
     
         88 . A method for administering a nitrogen mustard compound to a patient comprising the steps of
 a. contacting a stream of an intravenous infusion solution with a stream of a second solution comprising a nitrogen mustard compound over a time period of 30, 20, 10, 5 seconds or less;   b. mixing the solutions in a continuous mode of operation to provide a mixed solution; and   c. administering the mixed solution to the patient, thereby delivering the dose of the nitrogen mustard compound over a time period of 5, 10, 15, 20, 30, 45, 60 minutes.   
     
     
         89 - 90 . (canceled) 
     
     
         91 . An apparatus for mixing and administering of a nitrogen mustard compound comprising:
 a. a first reservoir containing an aqueous intravenous infusion solution;   b. a second reservoir containing a second, non-aqueous, solution comprising a nitrogen mustard compound;   c. a mixing device capable of mixing the intravenous infusion solution and the second solution;   d. a delivery device capable of delivering the mixed solution to the bloodstream of a patient;   e. a first vessel operably linking the first reservoir to the mixing device;   f. a second vessel operably linking the second reservoir to the mixing device; and   g. a third vessel operably linking the mixing device to the delivery device.   
     
     
         92 . The apparatus of  claim 91  further comprising a first pump capable of controlling the flow rate of the intravenous infusion solution and a second pump capable of controlling the flow rate of the second solution. 
     
     
         93 - 94 . (canceled) 
     
     
         95 . The apparatus of  claim 91  comprising drip valves, each configured to deliver the aqueous intravenous infusion solution or the second solution. 
     
     
         96 . The apparatus of  claim 91  comprising one or more pumps configured to deliver the aqueous intravenous infusion solution and the second solution. 
     
     
         96 . The apparatus of  claim 91  comprising a multichannel pump configured to deliver the aqueous intravenous infusion solution and the second solution. 
     
     
         97 . The apparatus of  claim 91  wherein the mixing device is selected from the group consisting of one or more tubes capable of mixing by gravity, agitation, convection, or a combination thereof. 
     
     
         98 . The apparatus of  claim 91  wherein the mixing device is one or more in-line mixers and/or tubes configured to mix the aqueous intravenous infusion solution and the second solution. [0144], [0148] 
     
     
         99 . The apparatus of  claim 91  wherein the delivery device is a catheter, an intravenous tube or vessel, or a needle. 
     
     
         100 . The apparatus of  claim 91  further comprising a control device to control the flow rate within the first and second vessels or the ratio of flow rates within the first and second vessels. 
     
     
         101 . The apparatus of  claim 91  wherein the intravenous infusion solution is 0.9% sodium chloride in Water for Injection (WFI); 0.9% sodium chloride and 5% dextrose in Water for Injection (WFI); or 0.45% sodium chloride and 2.5% dextrose in Water for Injection (WFI). 
     
     
         102 . The apparatus of  claim 91  wherein the second solution further comprises a polymer excipient or a polymer excipient 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 caprolactame, cellulose acetate, ethyl cellulose, methyl methacrylate, methacrylic acid, polymers and co-polymers thereof. 
     
     
         103 . The apparatus of  claim 91  wherein the second solution further comprises a solvent or a solvent selected from the group consisting of n-propanol, ethanol, iso-propanol, n-butanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl acetamide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, n-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), dimethylformamide (DMF), polyethylene glycol, propylene glycol, glycerin, and mixtures thereof. 
     
     
         104 . The apparatus of  claim 91  wherein the second solution comprises a saccharide excipient or a saccharide alcohol excipient, or an excipient selected from the group consisting of mannitol, maltitol, sorbitol, erythritol, xylitol, lactitol, lactose, sucrose, glycose, maltose, trehalose, dextrose, and combinations thereof. 
     
     
         105 . The apparatus of  claim 91  wherein the mixed solution comprises 0.2 to 4.0 mg/ml nitrogen mustard compound. 
     
     
         106 . The apparatus of  claim 91  wherein the nitrogen mustard compound is selected from the group consisting of cyclophosphamide, busulfan, chlorambucil, carmustin, melphalan, uramustine, ifosfamide, mechlorethamine, lumustine and salts and combinations thereof. 
     
     
         107 . The apparatus of  claim 91  wherein the nitrogen mustard compound is bendamustine. 
     
     
         108 . The apparatus of  claim 91  wherein the nitrogen mustard compound is bendamustine hydrochloride. 
     
     
         109 . An apparatus for mixing and administering of a nitrogen mustard compound comprising:
 a. a first reservoir containing an intravenous infusion solution;   b. a second reservoir containing a second solution comprising a nitrogen mustard compound and either 1) polyvinylpyrrolidone, or 2) mannitol and a non-aqueous solvent or a mixture of non-aqueous solvents;   c. a mixing device capable of mixing the intravenous infusion solution and the second solution so as to obtain a mixed solution with a constant concentration suitable for administration to a patient;   d. a delivery device capable of delivering the mixed solution to the bloodstream of a patient;   e. a first vessel operably linking the reservoir to the mixing device;   f. a second vessel operably linking the second reservoir to the mixing device; and   g. a third vessel operably linking the mixing device to the delivery device.   
     
     
         110 . The apparatus of  claim 108  further comprising a control device to control the flow rate within the first and second vessels or the ratio of the flow rates within the first and second vessel. 
     
     
         111 . The apparatus of  claim 109  wherein the mixing device is one or more in-line mixer(s) and/or tube(s) of appropriate volume configured to mix the aqueous intravenous infusion solution and the second solution. 
     
     
         112 . The apparatus of  claim 108 , wherein the second solution further comprises a polymer excipient 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, ethyl cellulose, methyl methacrylate, methacrylic acid, polymers and co-polymers thereof. 
     
     
         113 . The apparatus of  claim 108 , wherein the second solution further comprises a solvent selected from the group consisting of Water-for-Injection (WFI), n-propanol, ethanol, isopropanol, n-butanol, ethyl acetate, dimethyl carbonate, acetonitrile, dichloromethane, methyl ethyl ketone, methyl isobutyl ketone, 1-pentanol, methyl acetate, carbon tetrachloride, dimethyl acetamide, hexafluoroacetone, chlorobutanol, dimethyl sulfone, acetic acid, cyclohexane, n-methyl-2-pyrolidone (NMP), dimethylsulfoxide (DMSO), dimethylformamide (DMF), and mixtures thereof. 
     
     
         114 . A nitrogen mustard compound solution prepared by the steps of
 a. contacting a stream of an aqueous intravenous infusion solution continuously flowing at a controlled rate with a stream of a second, non-aqueous, solution comprising the nitrogen mustard compound continuously flowing at a second controlled rate; and   b. mixing the solutions to provide a uniform and continuously flowing stream of a mixed solution which provides a pharmaceutical dose of 0.2 to 4.0 mg/ml of the compound.   
     
     
         115 . A method for treating a medical condition in a patient comprising the steps of dissolving the preparation prepared according to  claim 114  in a pharmaceutically acceptable solvent to produce a pharmaceutically acceptable solution and administering to the patient a therapeutically effective amount of the solution, wherein the condition is amenable to treatment with the preparation. 
     
     
         116 . The method of treating according to  claim 115  wherein the condition is selected from the group consisting of chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, diffuse large B-cell lymphoma, breast cancer, small cell lung cancer, and/or an autoimmune disease. 
     
     
         117 . The method of treating according to  claim 114  comprising administering in combination with one or more antineoplastic agents. 
     
     
         118 . The method of treating according to  claim 117  wherein the antineoplastic agent is an antibody specific to CD20.