Colchicine compositions and methods

Abstract

Stable ultrapure colchicine compositions comprising ultrapure colchicine and a pharmaceutically acceptable excipient are described. The compositions can be tablets. Methods for preparing such compositions and methods of use are also disclosed. Methods of treating gout flares with colchicine compositions are also disclosed.

1 . A colchicine composition, comprising
 colchicine; and   a pharmaceutically acceptable excipient,   wherein the colchicine composition comprises no more than about 3.5% total impurities and no more than 0.42% N-deacetyl-N-formyl colchicine.   
   
   
       2 . The colchicine composition of  claim 1 , wherein administration of a single oral dose of the colchicine composition to a human in a fed or fasted state provides a maximum plasma colchicine concentration (Cmax) between about 1.3 ng/mL and about 4.0 ng/mL, a time after administration of colchicine at which Cmax is achieved (Tmax) of about 1.5±0.5 hr, an area under the plasma colchicine concentration curve from time 0 to time t (AUC 0-t ) between about 4.4 ng-hr/mL and about 30.8 ng-hr/mL, or an area under the plasma colchicine concentration curve from time 0 to infinity (AUC 0-INF ) between about 6.7 ng-hr/mL and about 27.8 ng-hr/mL. 
   
   
       3 . The colchicine composition of  claim 2 , wherein Cmax, AUC 0-t , or AUC 0-INF  are geometric mean values of ln transformed data determined in a population of at least 12 subjects and wherein Cmax is within about 80% to about 125% of 2.4 ng/mL, AUC 0-t  is within about 80% to about 125% of 11.3 ng-hr/mL, or AUC 0-INF  is within about 80% to about 125% of 12.9 ng-hr/mL. 
   
   
       4 . The colchicine composition of  claim 1  compressed into a tablet. 
   
   
       5 . The colchicine composition of  claim 4 , wherein the tablet further comprises a coating. 
   
   
       6 . The colchicine composition of  claim 1 , wherein the colchicine in the composition comprises no more than 3.0% total impurities, no more than about 0.15% per individual impurity of N-deacetyl-N-formyl colchicine (Impurity A), β-lumicolchicine (Impurity C), colchicoside (Impurity D), 3-O-demethyl colchicine (Impurity E), or colcheceine (Impurity F), and no more than about 2.0% of conformational isomer (Impurity B). 
   
   
       7 . The colchicine composition of  claim 1 , wherein administration of the composition to a human patient in a fed state provides an area under the plasma concentration curve (AUC) of colchicine in the fed state that is about 15% less than the AUC of colchicine after administration of the composition in the fasted state. 
   
   
       8 . The colchicine composition of  claim 1 , wherein the colchicine composition is such that a single dose of 0.6 mgA colchicine in the colchicine composition has enhanced colchicine bioavailability as compared to a single dose of a commercially available pharmaceutical product comprising 0.5 mg colchicine after dose-normalizing the 0.6 mgA colchicine to 0.5 mg colchicine, and
 wherein the enhanced bioavailability comprises a ratio of a geometric mean of logarithmic transformed AUC 0-∞ , AUC 0-t , or C max  of the composition to the pharmaceutical product of greater than about 1.25.   
   
   
       9 . The composition of  claim 1 , wherein the pharmaceutically acceptable excipient is a filler, a binder, a disintegrant, a lubricant, or a combination comprising at least one of the foregoing excipients. 
   
   
       10 . The composition of  claim 1 , wherein the filler is microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, dextrose, silicic acid, or a combination comprising at least one of the foregoing fillers. 
   
   
       11 . The composition of  claim 1 , wherein the binder is pregelatinized starch, carboxymethylcellulose, alignate, gelatin, polyvinylpyrrolidone, acacia, or a combination comprising at least one of the foregoing binders. 
   
   
       12 . The composition of  claim 1 , wherein the disintegrant is sodium starch glycolate, sodium croscarmellose (cross-linked carboxy methyl cellulose), crosslinked polyvinylpyrrolidone (PVP-XL), anhydrous calcium hydrogen phosphate, agar-agar, potato or tapioca starch, alginic acid, or a combination comprising at least one of the foregoing disintegrants. 
   
   
       13 . The composition of  claim 1 , wherein the lubricant is magnesium stearate, calcium stearate, or zinc stearate. 
   
   
       14 . The composition of  claim 6 , wherein the percent total impurities or the percent of individual Impurity A, B, C, D, or E in the colchicine is determined in an HPLC assay under the following conditions:
 the mobile phase is pH 4.5 Ammonium Acetate Buffer:methanol gradient;   the column is a Waters XBridge C18, 250 mm×4.6 mm, 5 μm particle size;   the flow rate is 0.9 mL/min;   the column temperature is 10±3.5 C and the sample temperature is 10±2 C;   the detection is at 246 nm;   the injection volume is 75 μL; and   the run time is 60 minutes;   and wherein the percent of Impurity F in the colchicine is determined in an HPLC assay under the following conditions:   
     
       
         
               
               
             
                   
               
                 HPLC System: 
                 HPLC equipped with a pump, auto sampler, 
               
                   
                 variable wavelength detector 
               
                   
                 and a suitable data acquisition system. 
               
                 Column: 
                 Phenomenex Gemini C18 150 mm × 4.6 mm 
               
                   
                 5 μm, 110 Å 
               
                 Detection: 
                 245 nm 
               
                 Flow Rate: 
                 About 1.5 mL/min 
               
                 Injection Volume: 
                 50 μL 
               
                 Temperature: 
                 Column: 10° C. ± 3.5° C. 
               
                   
                 Sample: 5° C. ± 2° C. 
               
                 Needle Rinse Setting: 
                 Double 
               
                 Needle Wash: 
                 Water:Acetonitrile (50:50) 
               
                 Digital Filter Response: 
                 1.0 
               
                 Sampling Rate: 
                 5.0 
               
                 Resolution: 
                 1.2 
               
                 Mobile Phase: 
                 pH 4.5 Buffer Solution:Acetonitrile (75:25) 
               
                 Run Time: 
                 About 7 minutes for Standard 
               
                   
                 About 20 minutes for first Blank and Samples. 
               
                   
               
           
              
             
             
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
   
   
       15 . The composition of  claim 1 , wherein the percent total impurities or the percent N-deacetyl-N-formyl colchicine in the composition is determined in an HPLC assay under the following conditions:
 the mobile phase is pH 4.5 Ammonium Acetate Buffer:methanol gradient;   the column is a Waters XBridge C18, 250 mm×4.6 mm, 5 μm particle size;   the flow rate is 0.9 mL/min;   the column temperature is 10±3.5 C and the sample temperature is 10±2 C;   the detection is at 246 nm;   the injection volume is 75 μL; and   the run time is 60 minutes.   
   
   
       16 . A method of treating a patient with the composition of  claim 1 , comprising administering the composition of  claim 1  to a patient,
 wherein the patient is a human patient and the patient has an acute gouty arthritis attack; acute or recurrent pericarditis; asthma; Behçet's disease; cancer; chronic gout; acystic disease comprising polycystic kidney disease or cystic fibrosis; a demyelinating disease of central or peripheral origin; Dupuytren's contracture; Familial Mediterranean fever; glaucoma, idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; an inflammatory disorder comprising rheumatoid arthritis; lentiviral infection; multiple sclerosis; postpericardiotomy syndrome; primary amyloidosis; primary biliary cirrhosis; proliferative vitreoretinopathy; or pyoderma gangrenosum; or the patient is in need of enhanced bone formation or bone mineral density.   
   
   
       17 . The method of  claim 16  wherein the patient is a patient suffering an acute gouty arthritis attack. 
   
   
       18 . The method of  claim 16  wherein the patient is a patient with chronic gout. 
   
   
       19 . The method of  claim 16  wherein the patient has familial Mediterranean fever.