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 method of administering colchicine to a patient comprising,
 administering a colchicine oral dosage form to a human patient in need thereof,   wherein the colchicine oral dosage form has equivalent bioavailability when administered to human subjects in a fed state or a fasted state, and   the equivalent bioavailability is established by a ratio of the geometric mean of logarithmic transformed area under the plasma colchicine concentration curve from time 0 to infinity (AUC 0-∞ ), area under the plasma colchicine concentration curve from time 0 to time t (AUC 0-t ), or maximum plasma colchicine concentration (C max ) in human subjects in the fasted state to that in human subjects in the fed state that is about 0.80 to about 1.25.   
   
   
       2 . The method of  claim 1 , wherein the patient is in need of prophylaxis of acute gout flares. 
   
   
       3 . The method of  claim 1 , wherein the patient is experiencing an acute gout flare. 
   
   
       4 . The method of  claim 1 , wherein the patient has Familial Mediterranean fever. 
   
   
       5 . The method of  claim 1 , wherein the colchicine oral dosage form comprises about 0.6 mgA colchicine. 
   
   
       6 . The method of  claim 1 , wherein after administration of the colchicine oral dosage form to human subjects each of the upper limit and the lower limit of the 90% confidence interval of the ratio of the geometric mean of logarithmic transformed C max  in the fed state to that in the fasted state is about 0.80 to about 1.25. 
   
   
       7 . The method of  claim 1  wherein the patient is in a fed state. 
   
   
       8 . The method of  claim 1  wherein a human in a fed state is a human within about 30 minutes after beginning to eat a meal; and a human in a fasted state is a human after a fast of at least about 10 hours. 
   
   
       9 . The method of  claim 1 , wherein the colchicine oral dosage form is such that a single dose of 0.6 mgA colchicine in the colchicine oral dosage form 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 area under the plasma colchicine concentration curve from time 0 to infinity (AUC 0-∞ ), area under the plasma colchicine concentration curve from time 0 to time t (AUC 0-t ), or maximum plasma colchicine concentration (C max ) of the colchicines oral dosage form to the commercially available pharmaceutical product of greater than about 1.25.   
   
   
       10 . The method of  claim 9 , wherein the pharmaceutical product comprising 0.5 mg colchicine further comprises 500 mg probenecid. 
   
   
       11 . The method of  claim 1 , wherein administration to a patient of a dosing regimen of 1.2 mgA colchicine in the oral dosage form followed by 0.6 mgA colchicine in the oral dosage form about one hour later provides an area under the plasma colchicine concentration curve from time 0 to infinity (AUC 0-∞ ) within about 80% to about 125% of 52.1 ng-hr/mL, an area under the plasma colchicine concentration curve from time 0 to time t (AUC 0-t ) within about 80% to about 125% of 43.8 ng-hr/mL, a maximum plasma colchicine concentration (C max ) within about 80% to about 125% of 6.2 ng/mL; or a time to maximum plasma colchicine concentration (T max ) within about 80% to about 125% of 1.8 hr. 
   
   
       12 . The method of  claim 1 , wherein the administration provides efficacy with reduced gastrointestinal side effect in a randomized, placebo-controlled study of a dosing regimen consisting of administration of 1.2 mgA colchicine in the oral dosage form followed by 0.6 mgA colchicine in the oral dosage form about one hour later, wherein patients taking colchicine show no significant difference in the frequency of occurrence of diarrhea as compared to patients taking placebo and showed efficacy significantly greater than placebo. 
   
   
       13 . The method of  claim 12 , wherein the odds of a patient experiencing diarrhea in response to the dosing regimen are not statistically different from the odds of a patient experiencing diarrhea in response to a placebo, whereas the odds of a patient experiencing diarrhea in response to a second dosing regimen of 1.2 mgA colchicine followed by 0.6 mgA colchicine about one hour later and every hour thereafter for 5 hours are statistically significantly higher than the odds of a patient experiencing diarrhea in response to a placebo. 
   
   
       14 . The method of  claim 12 , wherein the odds of a patient experiencing an acute gout flare being a responder to the dosing regimen are not statistically different from the odds of being a responder to a second dosing regimen of 1.2 mgA colchicine at the onset of the acute gout flare followed by 0.6 mgA colchicine about one hour later and every hour thereafter for 5 hours,
 wherein a responder is a patient obtaining a >50% improvement in pain at 24 hours after the dosing regimen without taking an additional active agent for reducing pain of the acute gout flare.