Colchine 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 - 109 . (canceled) 
   
   
       110 . A method of reducing side effects in a patient in need of colchicine therapy while maintaining efficacy, comprising
 administering less than about 2 mg of colchicine to a human patient over a period of about one hour, wherein the patient is experiencing an acute gouty arthritis attack,   wherein the odds of the patient experiencing diarrhea in response to the administered colchicine are not statistically different from the odds of the patient experiencing diarrhea in response to a placebo and   wherein the odds of the patient experiencing at least a 2-unit reduction in target joint pain at 24 hrs post-first dose in response to the administered colchicine are about 3.66 times the odds of the patient experiencing at least a 2-unit reduction in target joint pain at 24 hours (hrs) post-first dose in response to a placebo   
   
   
       111 - 112 . (canceled) 
   
   
       113 . The method of  claim 110 , wherein the colchicine is administered to the patient in a dosing regimen consisting of two colchicine tablets at the onset of the need for colchicine therapy, followed by one colchicine tablet in about one hour. 
   
   
       114 . The method of  claim 113 , wherein a colchicine tablet comprises about 0.6 mgA colchicine. 
   
   
       115 . The method of  claim 113 , wherein the colchicine is ultrapure colchicine comprising no more than about 3.0% total impurities and wherein the colchcine tablet comprises no more than about 3.5% total impurities and no more than about 0.42% N-deacetyl-N-formyl colchicine. 
   
   
       116 . The method of  claim 114 , wherein administration of the dosing regimen provides a maximum plasma colchicine concentration (Cmax) of about 3.2 ng/mL to about 11.4 ng/mL, a time after administration of colchicine at which Cmax is achieved (Tmax) of about 1.8±0.4 hr, an area under the plasma colchicine concentration curve from time 0 to time t (AUC 0-t ) of about 28.8 ng-hr/mL to about 58.9 ng-hr/mL, or an area under the plasma colchicine concentration curve from time 0 to infinity (AUC 0-INF ) of about 34.2 ng-hr/mL to about 74.1 ng-hr/mL. 
   
   
       117 - 150 . (canceled) 
   
   
       151 . A method of treating a patient in need of colchicine therapy, comprising
 administering to a patient in need of colchicine therapy a composition comprising colchicine and a pharmaceutically acceptable excipient,   wherein administration to a human of a single dose of the composition provides a Cmax between about 1.3 ng/mL and about 4.0 ng/mL, an AUC 0-t  between about 4.4 ng-hr/mL and about 30.8 ng-hr/mL, or an AUC 0-INF  between about 6.7 ng-hr/mL and about 27.8 ng-hr/mL.   
   
   
       152 . The method of  claim 151 , wherein Cmax, AUC 0-t , or AUC0 -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. 
   
   
       153 . The method of  claim 151 , wherein the colchicine composition comprises 0.6 mgA colchicine. 
   
   
       154 . The method of  claim 151 , wherein the colchicine composition is an oral dosage form. 
   
   
       155 . A method of treating a patient having an acute gouty arthritis attack, comprising
 administering a dosing regimen to a patient having an acute gouty arthritis attack,   wherein the dosing regimen consists of two colchicine tablets at the onset of the acute gouty arthritis attack, followed by one colchicine tablet in about one hour,   wherein a colchicine tablet comprises about 0.6 mgA colchicine,   wherein the odds of the patient experiencing at least a 2-unit reduction in target joint pain at 24 hrs post-first dose in response to the dosing regimen are about 3.66 times the odds of the patient experiencing at least a 2-unit reduction in target joint pain at 24 hours (hrs) post-first dose in response to a place.   
   
   
       156 . The method of  claim 155 , 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. 
   
   
       157 .- 161 . (canceled) 
   
   
       162 . A method of treating patients having an acute gouty arthritis attack, comprising
 administering a dosing regimen to a patient having an acute gouty arthritis attack,   wherein the dosing regimen consists of two colchicine tablets at the onset of the acute gouty arthritis attack, followed by one colchicine tablet in about one hour,   wherein a colchicine tablet comprises about 0.6 mgA colchicine,   wherein in a randomized, placebo-controlled study of the dosing regimen in patients with an acute gouty arthritis attack, the fraction of patients that experienced a given % improvement in pain at 24 hrs after first dose is shown in  FIG. 1 .   
   
   
       163 . 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.   
   
   
       164 .- 169 . (canceled) 
   
   
       170 . The composition of  claim 163 , 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. 
   
   
       171 . The composition of  claim 170 , 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. 
   
   
       172 . The composition of  claim 171 , wherein the filler is present in an amount of about 10 wt % to about 99 wt %, based on the total weight of the composition. 
   
   
       173 . The composition of  claim 170 , wherein the binder is pregelatinized starch, carboxymethylcellulose, alignate, gelatin, polyvinylpyrrolidone, acacia, or a combination comprising at least one of the foregoing binders. 
   
   
       174 . The composition of  claim 173 , wherein the binder is present in an amount of about 10 wt % to about 99 wt %, based on the total weight of the composition. 
   
   
       175 . The composition of  claim 170 , 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. 
   
   
       176 . The composition of  claim 175 , wherein the disintegrant is present in an amount of about 1 to about 20 wt %, based on the total weight of the composition. 
   
   
       177 . The colchicine composition of  claim 163 , wherein the colchicine is present in an amount of about 0.6 mgA. 
   
   
       178 . The colchicine composition of  claim 163  compressed into a tablet. 
   
   
       179 . The colchicine composition of  claim 163 , wherein the colchicine comprises no more than 3.0% total impurities and no more than 0.15% N-deacetyl-N-formyl colchicine. 
   
   
       180 . The colchicine composition of  claim 163 , wherein the percent total impurities or the percent N-deacetyl-N-formyl 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.   
   
   
       181 .- 187 . (canceled)