Stabilized hydroxyvitamin D

Abstract

The invention provides a stabilized 1α-hydroxyvitamin D (“SHVD”) which is particularly well suited for pharmaceutical formulations.

1 - 41 . (canceled)  
     
     
         42 . A method of making stabilized 1α-hydroxyvitamin D 2  comprising: a) tosylating the hydroxy group in the 3-position of a starting material which is a vitamin D compound to which a hydroxy is to be added in the 1α-position; b) converting the tosylated form to a cyclovitamin; c) hydroxylating the cyclovitamin in the 1α-position; d) converting the cyclovitamin to the cis and trans vitamin forms; e) irradiating the trans vitamin form to yield the cis form; f) recrystallizing the cis form in an organic solvent, g) milling the recrystallized cis form into a powder and vacuum oven drying the recrystallized form for 72-120 hours and at 55° C. to yield the stabilized 1α-hydroxyvitamin D 2 .  
     
     
         43 . A 1α-hydroxyvitamin D 2  synthesized by the method of  claim 42 .  
     
     
         44 - 50 . (canceled)  
     
     
         50 . A method as claimed in  claim 42 , wherein the organic solvent is methyl formate, ethyl formate, ethyl acetate, acetone, methylethylketone, hexane, 2-propanol-hexane, pentane, heptane, diethyl ether, diisopropyl ether, methanol, ethanol acetonitrile, or combinations thereof.  
     
     
         51 - 78 . (canceled)  
     
     
         79 . A pharmaceutical composition consisting essentially of 1α-hydroxyvitamin D 2  in a pharmaceutically acceptable carrier, wherein, relative to the amount of 1α-hydroxyvitamin D 2  present in the composition, 
 (i) impurities are present at no more than 2% (w/w) as determined by HPLC;    (ii) no single impurity is present in an amount greater than 0.5% (w/w); and    (iii) residual solvents from the process used to prepare the 1α-hydroxyvitamin D 2  are present in an amount of no more than 0.5% (w/w).    
     
     
         80 . The pharmaceutical composition of  claim 79  wherein the composition is in solid form.  
     
     
         81 . The pharmaceutical composition of  claim 79  wherein the composition is in solution form.  
     
     
         82 . The pharmaceutical composition of  claim 79  is suitable for oral administration.  
     
     
         83 . The pharmaceutical composition of  claim 79  is a soft gelatin capsule.  
     
     
         84 . The pharmaceutical composition of  claim 83  wherein the carrier comprises a pharmaceutically acceptable oil.  
     
     
         85 . The pharmaceutical composition of  claim 84  wherein the oil is fractionated coconut oil.  
     
     
         86 . The pharmaceutical composition of  claim 79  wherein the composition further comprises an antioxidant.  
     
     
         87 . The pharmaceutical composition of  claim 86 , wherein the antioxidant is butylated hydroxyanisole (BHA).  
     
     
         88 . The pharmaceutical composition of  claim 86 , wherein the antioxidant is butylated hydroxytoluene (BHT).  
     
     
         89 . The pharmaceutical composition of  claim 86 , wherein the antioxidant is vitamin E.  
     
     
         90 . The pharmaceutical composition of  claim 80 , wherein the solid form is a tablet.  
     
     
         91 . The pharmaceutical composition of  claim 80 , wherein the solid form is a granule.  
     
     
         92 . The pharmaceutical composition of  claim 80 , wherein the solid form is a powder.  
     
     
         93 . The pharmaceutical composition of claim  29  wherein the concentration of 1α-hydroxyvitamin D 2  is 0.5 μg to 25 μg.  
     
     
         94 . A process for making a pharmaceutical composition comprising combining a pharmaceutically acceptable carrier with a stabilized 1α-hydroxyvitamin D 2  characterized by a purity equal to or greater than 98% by a weight-based HPLC assay, residual solvents of 0.5% or less, a total impurity of 1.5% or less, and no single impurity of greater than 0.5%.  
     
     
         95 . A pharmaceutical composition made according to the process of  claim 94.