US2011190363A1PendingUtilityA1

Liquid formulations of bendamustine

Assignee: CEPHALON INCPriority: Sep 25, 2008Filed: Mar 15, 2011Published: Aug 4, 2011
Est. expirySep 25, 2028(~2.2 yrs left)· nominal 20-yr term from priority
A61K 47/18A61P 35/00A61K 47/40A61K 47/22A61K 9/0019A61K 47/10A61P 35/02A61K 47/20A61K 9/08A61K 31/4184
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Claims

Abstract

Stable liquid formulations of bendamustine, and pharmaceutically acceptable salts thereof, and polar aprotic solvents, are described.

Claims

exact text as granted — not AI-modified
1 . A liquid pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt or prodrug thereof, and a polar aprotic solvent. 
     
     
         2 . The formulation of  claim 1 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof. 
     
     
         3 . The formulation of  claim 1 , further comprising a non-aqueous polar protic solvent. 
     
     
         4 . The formulation of  claim 3 , wherein the non-aqueous polar protic solvent is an alcohol, a polyalkylene glycol, an amide, or a mixture thereof. 
     
     
         5 . The formulation of  claim 3 , wherein the non-aqueous polar protic solvent is an alcohol. 
     
     
         6 . The formulation of  claim 5 , wherein the alcohol is a glycol. 
     
     
         7 . The formulation of  claim 5 , wherein the alcohol is a cyclodextrin. 
     
     
         8 . The formulation of  claim 7 , wherein the cyclodextrin is hydroxypropyl-β-cyclodextrin. 
     
     
         9 . The formulation of  claim 3 , wherein the formulation comprises 90% or less, by volume of the formulation, of the non-aqueous polar protic solvent. 
     
     
         10 . The formulation of  claim 3 , wherein the polar aprotic solvent is dimethylacetamide and the nonaqueous polar protic solvent is propylene glycol. 
     
     
         11 . The formulation of  claim 1 , further comprising a pharmaceutically acceptable antioxidant. 
     
     
         12 . The formulation of  claim 1 , comprising about 5 mg/ml to about 200 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof. 
     
     
         13 . The formulation of  claim 1 , comprising about 5 mg/ml to about 120 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof. 
     
     
         14 . The formulation of  claim 1 , comprising at least about 5 mg/mL of bendamustine, or the pharmaceutically acceptable salt thereof. 
     
     
         15 . The formulation of  claim 1 , wherein the formulation is stable at about 5° C. for about 30 days to about 365 days. 
     
     
         16 . The formulation of  claim 1 , wherein the formulation is stable at about 5° C. for at least about 180 days. 
     
     
         17 . The formulation of  claim 1 , wherein analysis of the formulation indicates that the formulation contains no less than about 90% of the amount of bendamustine present prior to exposure to storage conditions. 
     
     
         18 . The formulation of  claim 1 , wherein analysis of the formulation indicates that the formulation contains no less than about 95% of the amount of bendamustine present prior to exposure to storage conditions. 
     
     
         19 . The formulation of  claim 17  where the storage conditions are about 5° C. for about 30 days to about 365 days. 
     
     
         20 . The formulation of  claim 17  where the storage conditions are about 5° C. for at least about 30 days. 
     
     
         21 . The formulation of  claim 17  where the storage conditions are about 5° C. for at least about 90 days. 
     
     
         22 . The formulation of  claim 17 , where the storage conditions are about 5° C. for at least about 180 days. 
     
     
         23 . The formulation of  claim 1 , further comprising at least one pharmaceutically acceptable excipient. 
     
     
         24 . The formulation of  claim 3 , further comprising at least one pharmaceutically acceptable excipient. 
     
     
         25 . The formulation of  claim 1 , further comprising an antioxidant, a surfactant, a lipid, a filler, an organic acid, a hydrophilic polymer, a complexing agent, a preservative, or a combination thereof. 
     
     
         26 . The formulation of  claim 3 , further comprising an antioxidant, a surfactant, a lipid, a filler, an organic acid, a hydrophilic polymer, a complexing agent, a preservative, or a combination thereof. 
     
     
         27 . The formulation of  claim 1 , further comprising at least one anti-neoplastic agent. 
     
     
         28 . The formulation of  claim 3 , further comprising at least one anti-neoplastic agent. 
     
     
         29 . The formulation of  claim 3 , wherein the formulation comprises 10 moles per liter, or less, of the non-aqueous polar protic solvent. 
     
     
         30 . The formulation of  claim 3 , wherein the formulation comprises between about 4 to about 9.5 moles per liter of the non-aqueous polar protic solvent. 
     
     
         31 . The formulation of  claim 3 , wherein the formulation comprises 90% or less, by volume of the formulation, of the non-aqueous polar protic solvent. 
     
     
         32 . The formulation of  claim 1 , comprising about 0.4% or less of HP1. 
     
     
         33 . The formulation of  claim 3 , comprising about 0.4% or less of HP1. 
     
     
         34 . The formulation of  claim 1 , comprising about 0.1% or less of HP1. 
     
     
         35 . The formulation of  claim 3 , comprising about 0.1% or less of HP1. 
     
     
         36 . The formulation of  claim 1 , comprising about 1.5% of less of DCE. 
     
     
         37 . The formulation of  claim 3 , comprising about 1.5% of less of DCE. 
     
     
         38 . The formulation of  claim 1 , comprising about 0.7% or less of BM1 dimer. 
     
     
         39 . The formulation of  claim 3 , comprising about 0.7% or less of BM1 dimer. 
     
     
         40 . The formulation of  claim 10 , comprising about 1.5% or less of PG-1, PG-2, or a combination thereof. 
     
     
         41 . A method of preparing an injectable formulation of bendamustine, or a pharmaceutically acceptable salt thereof, comprising:
 providing a liquid pharmaceutical formulation comprising bendamustine, or a pharmaceutically acceptable salt thereof, and a nonaqueous solvent;   diluting the liquid pharmaceutical formulation with a pharmaceutically acceptable injectable diluent.   
     
     
         42 . The method of  claim 41 , wherein the nonaqueous solvent is a polar aprotic solvent. 
     
     
         43 . The method of  claim 42 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof. 
     
     
         44 . The method of  claim 41 , wherein the liquid pharmaceutical formulation further comprising a non-aqueous polar protic solvent. 
     
     
         45 . The method of  claim 44 , wherein the nonaqueous polar protic solvent is an alcohol, a polyalkylene glycol, a primary amide, or a mixture thereof. 
     
     
         46 . The method of  claim 41  wherein the pharmaceutically acceptable injectable diluent is Sodium Chloride Injection. 
     
     
         47 . A method of treating cancer comprising
 identifying a patient in need of treatment of cancer;   providing a liquid pharmaceutical formulation comprising a therapeutically effective amount of bendamustine, or a pharmaceutically acceptable salt thereof, and nonaqueous solvent;   diluting the liquid pharmaceutical formulation with a pharmaceutically acceptable injectable diluent to form a pharmaceutical preparation;   administering the pharmaceutical preparation to the patient in need of treatment.   
     
     
         48 . The method of  claim 47 , wherein the nonaqueous solvent is a polar aprotic solvent. 
     
     
         49 . The method of  claim 48 , wherein the polar aprotic solvent is 1-methyl-2-pyrrolidone, 1,3-dimethyl-2-imidazolidinone, dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl formamide, propylene carbonate, or a mixture thereof. 
     
     
         50 . The method of  claim 47 , wherein the liquid pharmaceutical formulation further comprising a non-aqueous polar protic solvent. 
     
     
         51 . The method of  claim 50 , wherein the nonaqueous polar protic solvent is an alcohol, a polyalkylene glycol, a primary amide, or a mixture thereof. 
     
     
         52 . The method of  claim 47 , wherein the pharmaceutically acceptable injectable diluent is Sodium Chloride Injection.

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