Sustained-release formulations of colchicine and methods of using same

Abstract

Pharmaceutical compositions of colchicine for once-a-day oral administration are provided. The formulations comprise a sustained-release component and an optional immediate-release component, the compositions of which can be selectively adjusted, respectively, to release the active ingredient along a pre-determined or desired release profile. Method of treating or preventing cardiovascular disease and/or inflammatory disease in mammalian subjects comprising the administration of the novel formulations disclosed herein is also provided.

What is claimed is: 
     
         1 . A sustained release formulation of colchicine as an active ingredient, the formulation comprising:
 (a) colchicine or a pharmaceutically acceptable salt thereof;   (b) a retarding agent; and   (c) at least one pharmaceutically acceptable excipient.   
     
     
         2 . The formulation of  claim 1 , wherein the formulation releases at least about 80% of the colchicine in vitro within 24 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 3.5 hours, or within 1.5 hours. 
     
     
         3 . The formulation of  claim 1  or  2 , wherein the formulation releases at least about 20% of the colchicine in vitro within the first 30 minutes. 
     
     
         4 . The formulation of any one of  claims 1 - 3 , wherein the retarding agent is selected from a group consisting of cellulose ethers, cellulose esters, acrylic acid copolymers, waxes, gums, glyceryl fatty acid esters and sucrose fatty acid esters. 
     
     
         5 . The formulation of any one of  claims 1 - 4 , wherein the retarding agent contains hypromellose. 
     
     
         6 . The formulation of any one of  claims 1 - 5 , wherein the retarding agent is included in an amount between about 5 wt % and about 40 wt % of the formulation 
     
     
         7 . The formulation of any one of  claims 1 - 6 , wherein the pharmaceutically acceptable excipient is selected from a group consisting of a binder, a filling agent, a glidant, and a lubricant, or a combination thereof. 
     
     
         8 . The formulation of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable excipient is a binder selected from the group consisting of starches, gelatin, polyvinylpyrrolidone, cellulose derivatives, polyvinyl alcohol and mixtures thereof. 
     
     
         9 . The formulation of any one of  claims 1 - 8 , wherein the cellulose derivative is selected from a group consisting of hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC). 
     
     
         10 . The formulation of any one of  claims 1 - 9 , wherein the cellulose derivative forms a hydrophilic matrix. 
     
     
         11 . The formulation of any one of  claims 1 - 10 , wherein the pharmaceutically acceptable excipients is a filling agent selected from the group consisting of sucrose, lactose, in particular lactose monohydrate, trehalose, maltose, mannitol and sorbitol, croscarmellose sodium, crospovidone, alginic acid, sodium alginate, methacrylic acid DVB, cross-linked PVP, microcrystalline cellulose, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch, and combinations thereof. 
     
     
         12 . The formulation of any one of  claims 1 - 11 , wherein the total amount of filling agent in the formulation is between about 5.0 wt % and 90.0 wt % of the formulation. 
     
     
         13 . The formulation of any one of  claims 1 - 12 , wherein the pharmaceutically acceptable excipient is a glidant selected from the group consisting of colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, talc, and tribasic calcium phosphate 
     
     
         14 . The formulation of any one of  claims 1 - 13 , wherein total amount of glidant in the formulation is between about 0.5 wt % to about 5 wt % of the formulation. 
     
     
         15 . The formulation of any one of  claims 1 - 14 , wherein the pharmaceutically acceptable excipient is a lubricant selected from the group consisting of glyceryl behenate, stearic acid, hydrogenated vegetable oils, stearyl alcohol, leucine, polyethylene glycol, magnesium stearate, glyceryl monostearate, polyethylene glycol, ethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, DL-leucine, and colloidal silica. 
     
     
         16 . The formulation of any one of  claims 1 - 5 , wherein the lubricant is included in an amount between about 0.5 wt % to about 5 wt % of the formulation. 
     
     
         17 . The formulation of any one of  claims 1 - 16 , wherein the formulation is in a dosage form selected from the group consisting of a tablet, a pill, a capsule, a caplet, a suppository, a dermal patch, a cream, sublingual formulation, eye drops, gel, ointment, a troche, a pouch, sprinkles, or in fixed combination with a surgically insertable medical device. 
     
     
         18 . The formulation of any one of  claims 1 - 17 , wherein the dosage form is a tablet. 
     
     
         19 . The formulation of any one of  claims 1 - 18 , wherein the compression strength of the tablet is between about 30N and about 130N. 
     
     
         20 . The formulation of any one of  claims 1 - 19 , wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg per dose. 
     
     
         21 . The formulation of any one of  claims 1 - 20 , wherein the amount of colchicine per dose is between 0.1 mg to 2.0 mg, 0.1 mg to 1.75 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.25 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or more than 0.25 mg and less than 0.5 mg. 
     
     
         22 . The formulation of any one of  claims 1 - 21 , wherein the total amount of colchicine in the formulation is between about 0.25 wt % and about 0.75 wt % of the formulation. 
     
     
         23 . The formulation of any one of  claims 1 - 22  for use in preventing and/or treating a cardiovascular disease. 
     
     
         24 . The formulation of any one of  claims 1 - 23 , wherein the cardiovascular disease is selected from the group consisting of acute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome (PPS) and cardiovascular events in patients with stable coronary disease. 
     
     
         25 . The formulation of any one of  claims 1 - 24 , for use in combination with conventional therapy for the long-term prevention of an acute cardiovascular event in patients with established stable coronary disease. 
     
     
         26 . The formulation of any one of  claims 1 - 25 , wherein said acute cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke. 
     
     
         27 . The formulation of any one of  claims 1 - 26 , wherein the conventional therapy includes the administration of a colchicine-compatible statin. 
     
     
         28 . The formulation of any one of  claims 1 - 27 , wherein the colchicine-compatible statin is administered in a fixed or unfixed combination with colchicine. 
     
     
         29 . The formulation of any one of  claims 1 - 28 , wherein the colchicine-compatible statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin, a derivative or a salt thereof. 
     
     
         30 . The formulation of any one of  claims 1 - 22  for use in preventing and/or treating an inflammatory disease. 
     
     
         31 . The formulation of any one of  claims 1 - 22  and  30 , wherein the inflammatory disease is selected from the group consisting of gout, familial Mediterranean fever, Behcet's disease, Age-related macular degeneration and Alzheimer's disease. 
     
     
         32 . The formulation according to any one of  claims 1 - 22  and  30 - 31 , wherein the total daily dose of colchicine administered to a subject is no more than about 0.75 mg. 
     
     
         33 . A method for treating and/or preventing a cardiovascular disease in a subject, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of colchicine according to any one of  claims 1 - 22 . 
     
     
         34 . The method of  claim 33 , wherein the cardiovascular disease is selected from the group consisting of acute pericarditis, recurrent pericarditis, post-pericardiotomy syndrome (PPS) and cardiovascular events in patients with stable coronary disease. 
     
     
         35 . The method of  claims 33  and  34 , wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg per dose. 
     
     
         36 . The method of any one of  claims 33 - 35 , wherein the amount of colchicine per dose is between 0.1 mg to 2.0 mg, 0.1 mg to 1.75 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.25 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or more than 0.25 mg and less than 0.5 mg. 
     
     
         37 . The method of any one of  claims 33 - 36 , wherein the total daily dose of colchicine administered to the subject is no more than about 0.75 mg. 
     
     
         38 . The method of any one of  claims 33 - 37 , further comprising administering to the subject a conventional therapy for the long-term prevention of an acute cardiovascular event in patients with established stable coronary disease. 
     
     
         39 . The method of any one of  claims 33 - 38 , wherein the acute cardiovascular event is acute coronary syndrome, out-of-hospital cardiac arrest or noncardioembolic ischemic stroke. 
     
     
         40 . The method of any one of  claims 33 - 39 , wherein the conventional therapy includes the administration of a colchicine-compatible statin. 
     
     
         41 . The method of any one of  claims 33 - 40 , wherein the colchicine-compatible statin is selected from the group consisting of atorvastatin, rosuvastatin, simvastatin and pravastatin, a derivative or a salt thereof. 
     
     
         42 . A method for treating and/or preventing an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of a sustained release formulation of colchicine according to any one of  claims 1 - 22 . 
     
     
         43 . The method of  claim 42 , wherein the inflammatory disease is selected from the group consisting of gout, familial Mediterranean fever, Behcet's disease, Age-related macular degeneration and Alzheimer's disease. 
     
     
         44 . The method of  claims 42  and  43 , wherein the total amount of colchicine in the formulation is from about 0.1 to about 5.0 mg per dose. 
     
     
         45 . The method of any one of  claims 42 - 44 , wherein the amount of colchicine per dose is between 0.1 mg to 2.0 mg, 0.1 mg to 1.75 mg, 0.1 mg to 1.5 mg, 0.1 mg to 1.25 mg, 0.1 mg to 1.0 mg, 0.1 mg to 0.75 mg, 0.1 mg to 0.6 mg, 0.1 mg to 0.5 mg or more than 0.25 mg and less than 0.5 mg. 
     
     
         46 . The method of any one of  claims 42 - 45 , wherein the total daily dose of colchicine administered to the subject is no more than about 0.75 mg. 
     
     
         47 . A process of preparing a colchicine-sustained release tablet comprising:
 (A) forming a granuate by dissolving about 0.25 to about 0.75% weight of the total composition of colchicine in an acceptable solvent, water and   (B) adding a binder and a filling agent to Step A, and forming a wet granulate;   (C) drying the wet granulate of Step B;   (D) blending the dried granulate from Step C with a retarding agent, a filling agent, a glidant and a lubricant; and   (E) compressing the final granulation from step D into a tablet.   
     
     
         48 . The process of  claim 47  wherein:
 in Step A the binder is Hypromellose; 
 in Step B the filling agent used is lactose monohydrate and Pregelatinized Starch; and 
 in Step D the retarding agent used is Retalac; the filing agent used is lactose monohydrate, the glidant used is Talc, and the lubricant used is Stearic acid. 
 
     
     
         49 . The process of  claims 47  and  48 , wherein the specific ingredients and amounts used are: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Ingredient 
                   mg/Tablet 
                   Tablet % 
                 
                     
                     
                 
                     
                 
                 
                 
                 
                 
               
                     
                   Colchicine 
                   0.500 
                   0.5 
                 
                     
                   Lactose monohydrate 
                   59.00 
                   59.0 
                 
                     
                   Pregelatinized Starch 
                   7.50 
                   7.5 
                 
                     
                   Hypromellose 6 mPa*s 
                   1.000 
                   1.0 
                 
                     
                   Purified water 1   
                   q.s. 
                   q.s. 
                 
                     
                   Retalac (Compound of 
                   5.0-40.00 
                   5.0-40.0 
                 
                     
                   Lactose monohydrate 
                 
                     
                   and Hypromellose 
                 
                     
                   4000 mPa*s 
                 
                     
                   50/50 w/w %) 
                 
                     
                   Talc 
                   1.00 
                   1.0 
                 
                     
                   Stearic acid 50 
                   1.00 
                   1.0 
                 
                     
                   Total tablet weight 
                   100.00 
                 
                     
                   [mg]: 
                 
                     
                     
                 
             
                
                
                
               
               
                
               
            
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         50 . A shaped and compressed sustained release therapeutic composition comprising colchicine and excipients combined into a matrix, wherein the excipients comprise Hypromellose, and wherein the total amount of excipients is effective to bind the colchicine in a sustained release solid matrix and is at least about 99 percent of the weight of said shaped and compressed composition. 
     
     
         51 . The sustained release therapeutic composition of  claim 50 , wherein the composition releases at least about 80% of the colchicine in vitro within 24 hours, within 16 hours, within 12 hours, within 8 hours, within 6 hours, within 4 hours, within 3.5 hours, or within 1.5 hours. 
     
     
         52 . The sustained release therapeutic composition of  claims 50  and  51 , wherein the composition releases at least about 20% of the colchicine in vitro within the first 30 minutes. 
     
     
         53 . A shaped and compressed colchicine sustained release tablet made by wet granulating a sufficient amount of colchicine to comprise from about 0.25 to about 0.75 percent weight of the total composition with the excipients wherein the excipients comprise the following: 
       
         
           
                 
                 
                 
               
                     
                     
                 
                     
                   Ingredient 
                   % Range 
                 
                     
                     
                 
                     
                   Lactose monohydrate 
                   10-80  
                 
                     
                   Pregelatinized Starch 
                   5-50 
                 
                     
                   Hypromellose 6 mPa*s 
                   1-30 
                 
                     
                   Purified water 1   
                   q.s. 
                 
                     
                   Retalac (Compound of 
                   5-40 
                 
                     
                   Lactose monohydrate 
                 
                     
                   and Hypromellose 
                 
                     
                   4000 mPa*s 
                 
                     
                   50/50 w/w %) 
                 
                     
                   Talc 
                   0.5-5   
                 
                     
                   Stearic acid 50 
                   0.5-5   
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         54 . A composition of  claim 53  wherein the total amount of excipients is at least about 99 percent of the total weight of said shaped and compressed composition. 
     
     
         55 . A method of treating a patient having a cardiovascular disease, the method consisting of: orally administering 0.5 mg colchicine to a human patient, the method providing a maximum colchicine blood plasma concentration (Cmax) in a range of about 0.5 to 5 ng/mL, and a time after the first administration at which Cmax is reached (Tmax) of about 1.5 to 8 hr. 
     
     
         56 . The method of  claim 55 , the method further providing an area under the curve of colchicine plasma concentration versus time from time 0 to time t (AUC0-t), where t is the last time point with a measurable colchicine plasma concentration, in a range of about 4 to 20 ng-hr/mL. 
     
     
         57 . The method of  claims 55  and  56 , the method further providing an area under the curve of colchicine plasma concentration versus time from time 0 to time infinity (AUC0-∞) in a range of 4 to 20 ng-hr/mL. 
     
     
         58 . The method of any one of  claims 55 - 57 , the method further providing an area under the curve of colchicine plasma concentration versus time from time 0 to time t (AUC0-t), where t is the last time point with a measurable colchicine plasma concentration, in a range of about 4 to 20 ng-hr/mL and an area under the curve of colchicine plasma concentration versus time from time 0 to time infinity (AUC0-∞) in a range of about 4 to 20 ng-hr/mL. 
     
     
         59 . The method of any one of  claims 55 - 58 , wherein each said orally administering comprises administering one or more dosage forms each containing 0.5 mg colchicine. 
     
     
         60 . The method of any one of  claims 55 - 59 , wherein the dosage form is a tablet. 
     
     
         61 . The method of any one of  claims 55 - 60 , wherein the tablet is a sustained release tablet. 
     
     
         62 . A method of treating a patient with a cardiovascular disease, comprising administering to the patient an adjusted daily dosage amount of colchicine based on the weight of the patient, wherein the adjusted daily dosage amount of colchicine is about 50% to about 300% of 0.5 mg per day, which is suitable for the patient if the patient weighs about 70 kg. 
     
     
         63 . The formulation of  claim 1  or  2 , wherein the formulation releases at least about 80% of the colchicine in vitro in between about 1.5 and about 3.5 hours.