Pulsatile release histamine H2 antagonist dosage form

Abstract

A unit dosage form, such as a capsule or the like, for delivering drugs into the body in a circadian release fashion comprising one or more populations of drug-containing particles (beads, pellets, granules, etc.) is disclosed. Each bead population exhibits a pre-designed rapid or sustained release profile with or without a predetermined lag time of 3 to 5 hours. Such a circadian rhythm release drug delivery system is designed to provide a plasma concentration—time profile, which varies according to physiological need at different times during the dosing period, i.e., mimicking the circadian rhythm and severity/manifestation of gastric acid secretion (and/or midnight gerd), predicted based on pharmaco-kinetic and pharmaco-dynamic considerations and in vitro/in vivo correlations.

We claim:  
     
         1 . A histamine H 2  antagonist pharmaceutical dosage form providing a bi-modal pulsatile release profile comprising: 
 a. immediate release (IR) beads comprising an active-containing core particle; and    b. timed pulsatile release (TPR) beads, wherein said TPR beads comprise: 
 i. an active-containing core particle; and  
 ii. a pulse coating surrounding said core, 
 wherein said IR beads provides a therapeutically effective amount of active to treat gastric acid secretions and the TPR beads provide a delayed dose of active which provides a therapeutically effective amount of active to treat midnight GERD.  
 
   
     
     
         2 . A pharmaceutical dosage form as defined in  claim 1 , wherein said histamine H 2  receptor antagonist is selected from the group consisting of nizatidine, cimetidine, ranitidine, and famotidine and derivatives thereof.  
     
     
         3 . A pharmaceutical dosage form as defined in  claim 1 , wherein said timed pulsatile release (TPR) beads when tested in a USP Type II apparatus at 50 rpm using a 2-stage dissolution medium (first 2 hours and 700 ml 0.1 N HCl at 37° C. followed by a dissolution in a pH of 6.8 obtained by the addition of 200 ml of pH modifier) exhibits a dissolution profile substantially corresponding to the following pattern: 
 after 2 hours, 0-25% of the total active is released;  
 after 3 hours, 15-80% of the total active is released; and  
 after 4 hours, not less than 60% of the total active is released.  
 
     
     
         4 . A pharmaceutical dosage form as defined in  claim 3 , wherein said dissolution profile substantially corresponds to the following pattern: 
 after 2 hours, 0-15% of the total active is released;    after 3 hours, 20-65% of the total active is released; and    after 4 hours, not less than 70% of the total active is released.    
     
     
         5 . A pharmaceutical dosage form as defined in  claim 4 , wherein said dissolution profile substantially corresponds to the following pattern: 
 after 2 hours, 0-5% of the total active is released;    after 3 hours, 30-50% of the total active is released; and    after 4 hours, not less than 80% of the total active is released.    
     
     
         6 . A pharmaceutical dosage form as defined in  claim 1 , wherein said pulse coating comprises a water insoluble polymer and an enteric polymer.  
     
     
         7 . A pharmaceutical dosage form as defined in  claim 6 , wherein said enteric polymer selected from the group consisting of esters of cellulose, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers, shellac and derivatives thereof.  
     
     
         8 . A pharmaceutical dosage form as defined in  claim 7 , wherein said enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate and combinations thereof.  
     
     
         9 . A pharmaceutical dosage form as defined in  claim 1 , wherein at least one of said polymers further comprises a plasticizer.  
     
     
         10 . A pharmaceutical dosage form as defined in  claim 9 , wherein said plasticizer is selected from the group of triacetin, tributyl citrate, tri-ethyl citrate, acetyl tri-n-butyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol, polypropylene glycol, castor oil and acetylated mono- and di-glycerides and mixtures thereof.  
     
     
         11 . A dosage form as defined in  claim 6 , wherein said water insoluble polymer and said enteric polymer are present in said pulse release coating at a ratio from 4:1 to 1:2.  
     
     
         12 . A dosage form as defined in  claim 11 , wherein said ratio of water insoluble polymer to enteric polymer is from 2:1 to 1:1.  
     
     
         13 . A dosage form as defined in  claim 11 , wherein said water insoluble polymer is ethylcellulose and said enteric polymer is hydroxypropyl methylcellulose phthalate.  
     
     
         14 . A dosage form as defined in  claim 13 , wherein said ratio is approximately 1:1.  
     
     
         15 . A dosage form as defined in  claim 1 , wherein said IR beads provide a loading dose by releasing substantially all of the active contained in said IR beads within the first hour after administration of the dosage form.  
     
     
         16 . A dosage form as defined in  claim 1 , wherein said IR beads and TPR beads are present in a ratio from about 3:1 to 1:3.  
     
     
         17 . A dosage form as defined in  claim 16 , wherein said IR beads and TPR beads are present in a ratio from about 2:1 to 1:2.  
     
     
         18 . A dosage form as defined in  claim 1 , wherein the total weight of the coatings on the TPR beads is 10-60 weight % based on the total weight of the coated particles.  
     
     
         19 . A method for the preparation of the dosage form of  claim 1 , comprising the steps of: 
 a. preparing an active-containing core to form IR beads;    b. coating the IR bead with a mixture of plasticized water soluble polymer and an enteric polymer to form a TPR bead; and    c. filling capsules with IR beads and TPR beads at a ratio from 3:1 to 1:3.    
     
     
         20 . The method of  claim 19 , wherein said active-containing core is produced by coating a particle selected from the group consisting of non-pareil seeds, acidic buffer crystals and alkaline buffer crystals with a water soluble film-forming composition comprising nizatidine and a polymeric binder.