Stable dosage forms of levomilnacipran

Abstract

The present invention relates to stable dosage forms of levomilnacipran and pharmaceutically acceptable salts thereof. Processes for the preparation of these dosage forms and methods of using these dosage forms are also described.

1 - 23 . (canceled) 
     
     
         24 . A method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient about 120 mg/day of levomilnacipran or a pharmaceutically acceptable salt thereof in one or more sustained release oral dosage forms,
 wherein the administering step provides a therapeutic blood plasma level of levomilnacipran or pharmaceutically acceptable salt thereof over approximately a twenty-four hour period to treat major depressive disorder in the patient, and   wherein the administering step provides an average maximum plasma concentration (C max ) between about 50 ng/mL and about 350 ng/mL of levomilnacipran or pharmaceutically acceptable salt thereof, an AUC 0-∞  between about 1000 ng·hr/mL and about 9000 ng·hr/mL, and a T max  of at least 3 hours to the patient, and   wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic peaks at about 6.0±0.2 degrees 2θ and at about 12.0±0.2 degrees 2θ.   
     
     
         25 . The method of  claim 24 , wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 20.1±0.2 degrees 2 θ and/or about 22.5±0.2 degrees 2θ. 
     
     
         26 . The method of  claim 25 , wherein the X-ray powder diffraction pattern comprises characteristic peaks at about 20.1±0.2 degrees 2θ and at about 22.5±0.2 degrees 2θ. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . A method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient about 120 mg/day of levomilnacipran or a pharmaceutically acceptable salt thereof in one or more sustained release oral dosage forms,
 wherein the administering step provides a therapeutic blood plasma level of levomilnacipran or pharmaceutically acceptable salt thereof over approximately a twenty-four hour period to treat major depressive disorder in the patient, and   wherein the administering step provides a mean plasma concentration of levomilnacipran or pharmaceutically acceptable salt thereof over time (AUC 0-∞ ) between about 1000 ng·hr/mL and about 9000 ng·hr/mL and a T max  of at least 3 hours to the patient, and   wherein the one or more sustained release oral dosage forms comprise levomilnacipran or pharmaceutically acceptable salt thereof which is crystalline in structure.   
     
     
         31 . The method of  claim 30 , wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic peaks at about 6.0±0.2 degrees 2θ and at about 12.0±0.2 degrees 2θ. 
     
     
         32 . The method of  claim 31 , wherein the X-ray powder diffraction pattern further comprises characteristic peaks at about 20.1±0.2 degrees 2θ and/or about 22.5±0.2 degrees 2θ. 
     
     
         33 . The method of  claim 32 , wherein the X-ray powder diffraction pattern comprises characteristic peaks at about 20.1±0.2 degrees 2θ and at about 22.5±0.2 degrees 2θ. 
     
     
         34 . The method of  claim 30 , wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic d spacing values of about 7.4 Å and about 14.8 Å. 
     
     
         35 . The method of  claim 34 , wherein the X-ray powder diffraction pattern comprises d spacing values at about 4.0 Å and/or about 4.4 Å. 
     
     
         36 . The method of  claim 30 , wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. 
     
     
         37 . The method of  claim 36 , wherein the one or more sustained release oral dosage forms release less than about 60% of the levomilnacipran or pharmaceutically acceptable salt thereof contained therein after about 2 hours following entry into deionized water at a temperature of about 37° C. and subjected to USP apparatus II at 75 rpm. 
     
     
         38 . A method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient about 120 mg/day of levomilnacipran or a pharmaceutically acceptable salt thereof in one or more sustained release oral dosage forms,
 wherein the administering step provides a therapeutic blood plasma level of levomilnacipran or pharmaceutically acceptable salt thereof over approximately a twenty-four hour period to treat major depressive disorder in the patient, and   wherein the administering step provides a mean plasma concentration of levomilnacipran or pharmaceutically acceptable salt thereof over time (AUC 0-∞ ) between about 1000 ng·hr/mL and about 9000 ng·hr/mL and a T max  of at least 3 hours to the patient, and   wherein the one or more sustained release oral dosage forms release less than about 60% of the levomilnacipran or pharmaceutically acceptable salt thereof contained therein after about 2 hours following entry into deionized water at a temperature of about 37° C. and subjected to USP apparatus II at 75 rpm.   
     
     
         39 . The method of  claim 38 , wherein the one or more sustained release oral dosage forms release less than about 80% of the levomilnacipran or pharmaceutically acceptable salt thereof contained therein after about 4 hours following entry into deionized water at a temperature of about 37° C. and subjected to USP apparatus II at 75 rpm. 
     
     
         40 . The method of  claim 38 , wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. 
     
     
         41 . A method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient about 120 mg/day of levomilnacipran or a pharmaceutically acceptable salt thereof in one or more sustained release oral dosage forms,
 wherein the administering step provides a therapeutic blood plasma level of levomilnacipran or pharmaceutically acceptable salt thereof over approximately a twenty-four hour period to treat major depressive disorder in the patient, and   wherein the administering step provides a mean plasma concentration of levomilnacipran or pharmaceutically acceptable salt thereof over time (AUC 0-∞ ) between about 1000 ng·hr/mL and about 9000 ng·hr/mL and a T max  of at least 3 hours to the patient, and   wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide.   
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 31 , wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. 
     
     
         44 . The method of  claim 43 , wherein the administering step further comprises administering within the sustained-release oral dosage forms between about 0.001% and about 0.2 wt. % of (1S,5R) 1-phenyl-3-azabicyclo[3-1-0]hexane-2-one relative to the amount of levomilnacipran or salt thereof. 
     
     
         45 . The method of  claim 33 , wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. 
     
     
         46 . The method of  claim 45 , wherein the administering step further comprises administering within the sustained-release oral dosage forms between about 0.001% and about 0.2 wt. % of (1S,5R) 1-phenyl-3-azabicyclo[3-1-0]hexane-2-one relative to the amount of levomilnacipran or salt thereof. 
     
     
         47 . The method of  claim 30 , wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic peaks at about 12.0±0.2 degrees 2θ and at about 20.1±0.2 degrees 2θ. 
     
     
         48 . The method of  claim 47 , wherein the X-ray powder diffraction pattern further comprises a characteristic peak at about 22.5±0.2 degrees 2θ. 
     
     
         49 . The method of  claim 47 , wherein the one or more sustained release oral dosage forms comprise at most 2% by weight relative to the weight of levomilnacipran or pharmaceutically acceptable salt thereof of a total combined amount of other isomers of 2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide and degradants of (1S,2R)-2-(amino methyl)-N,N-diethyl-1-phenyl cyclopropane carboxamide. 
     
     
         50 . The method of  claim 49 , wherein the administering step further comprises administering within the sustained-release oral dosage forms between about 0.001% and about 0.2 wt. % of (1S,5R)1-phenyl-3-azabicyclo[3-1-0]hexane-2-one relative to the amount of levomilnacipran or salt thereof. 
     
     
         51 . The method of  claim 50 , wherein the one or more sustained release oral dosage forms release less than about 60% of the levomilnacipran or pharmaceutically acceptable salt thereof contained therein after about 2 hours following entry into deionized water at a temperature of about 37° C. and subjected to USP apparatus II at 75 rpm. 
     
     
         52 . The method of  claim 41 , wherein the administering step further comprises administering within the sustained-release oral dosage forms between about 0.001% and about 0.2 wt. % of (1S,5R)1-phenyl-3-azabicyclo[3-1-0]hexane-2-one relative to the amount of levomilnacipran or salt thereof. 
     
     
         53 . A method for treating major depressive disorder in a patient in need thereof, comprising administering to the patient about 120 mg/day of levomilnacipran or a pharmaceutically acceptable salt thereof in one or more sustained release oral dosage forms,
 wherein the administering step provides a therapeutic blood plasma level of levomilnacipran or pharmaceutically acceptable salt thereof over approximately a twenty-four hour period to treat major depressive disorder in the patient, and   wherein the administering step provides a mean plasma concentration of levomilnacipran or pharmaceutically acceptable salt thereof over time (AUC 0-∞ ) between about 1000 ng·hr/mL and about 9000 ng·hr/mL and a T max  of at least 3 hours to the patient, and   wherein the administering step further comprises administering within the one or more sustained-release oral dosage forms between about 0.001% and about 0.2 wt. % of (1S,5R)1-phenyl-3-azabicyclo[3-1-0]hexane-2-one relative to the amount of levomilnacipran or salt thereof.   
     
     
         54 . The method of  claim 53 , wherein the one or more sustained release oral dosage forms comprise levomilnacipran or pharmaceutically acceptable salt thereof which is crystalline in structure. 
     
     
         55 . The method of  claim 53 , wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic peaks at about 6.0±0.2 degrees 2θ and at about 12.0±0.2 degrees 2θ. 
     
     
         56 . The method of  claim 53 , wherein the one or more sustained release oral dosage forms have an X-ray powder diffraction pattern comprising characteristic peaks at about 12.0±0.2 degrees 2θ and at about 20.1±0.2 degrees 2θ. 
     
     
         57 . The method of  claim 55 , wherein the X-ray powder diffraction pattern comprises a characteristic peak at about 20.1±0.2 degrees 2θ. 
     
     
         58 . The method of  claim 56 , wherein the X-ray powder diffraction pattern comprises a characteristic peak at about 22.5±0.2 degrees 2θ.