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.

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 provide 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, about 0-25% of the total active is released;   after 3 hours, about 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, about 0-15% of the total active is released;   after 3 hours, about 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, about 0-5% of the total active is released;   after 3 hours, about 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 is 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 6 , 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 coating at a ratio from about 4:1 to about 1:2. 
     
     
         12 . A dosage form as defined in  claim 11 , wherein said ratio of water insoluble polymer to enteric polymer is from about 2:1 to about 1:2. 
     
     
         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 about 1:1. 
     
     
         15 . A dosage form as defined in  claim 1 , wherein said IR beads release substantially all of the active contained therein 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 about 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 about 1:2. 
     
     
         18 . A dosage form as defined in  claim 1 , wherein the total weight of the coating on the TPR beads is about 10-60 weight % based on the total weight of the TPR beads. 
     
     
         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 a fraction of the IR beads with a water insoluble polymer and an enteric polymer to form TPR beads; and   c. filling capsules with IR beads and TPR beads at a ratio from about 3:1 to about 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. 
     
     
         21 . The method of  claim 19 , wherein said active-containing core is produced by granulating and milling and/or by extruding and spheronizing a polymer composition containing nizatidine. 
     
     
         22 . A pulsatile release nizatidine dosage form comprising:
 a. immediate release (IR) beads comprising a nizatidine-containing core particle; and   b. timed pulsatile release (TPR) beads, wherein said TPR beads comprise:
 i. a nizatidine-containing core particle; 
 ii. a pulse coating surrounding said core, said pulse coating comprising ethylcellulose and an enteric polymer; 
   wherein said 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, about 0-25% of the total nizatidine is released;   after 3 hours, about 15-80% of the total nizatidine is released; and   after 4 hours, not less than 60% of the total nizatidine is released.   
     
     
         23 . A pharmaceutical dosage form as defined in  claim 22 , wherein said dissolution profile substantially corresponds to the following pattern:
 after 2 hours, about 0-15% of the total nizatidine is released;   after 3 hours, about 20-65% of the total nizatidine is released; and   after 4 hours, not less than 70% of the total nizatidine is released.   
     
     
         24 . A pharmaceutical dosage form as defined in  claim 22 , wherein the dissolution profile substantially corresponds to the following pattern:
 after 2 hours, about 0-5% of the total nizatidine is released;   after 3 hours, about 30-50% of the total nizatidine is released; and   after 4 hours, not less than 80% of the total nizatidine is released.   
     
     
         25 . A pharmaceutical dosage form as defined in  claim 22 , wherein the core particle is a non-pareil sugar seed coated with nizatidine and a polymeric binder, or the core particle is prepared by granulating and milling and/or by extruding and spheronizing a polymer composition containing nizatidine, to form a core particle containing nizatidine. 
     
     
         26 . A pharmaceutical dosage form as defined in  claim 22 , wherein said enteric polymer is selected from the group consisting of esters of cellulose, polyvinyl acetate phthalate, pH-sensitive methacrylic acid-methylmethacrylate copolymers, shellac and derivatives thereof. 
     
     
         27 . A pharmaceutical dosage form as defined in  claim 26 , wherein said enteric polymer is selected from the group consisting of cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate and combinations thereof. 
     
     
         28 . A pharmaceutical dosage form as defined in  claim 22 , wherein said pulse coating further comprises a plasticizer. 
     
     
         29 . A pharmaceutical dosage form as defined in  claim 28  wherein said plasticizer is selected from the group consisting 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. 
     
     
         30 . A pharmaceutical dosage form as defined in  claim 22 , wherein said ethylcellulose and said enteric polymer are present in said pulse release coating at a ratio from about 4:1 to about 1:2. 
     
     
         31 . A pharmaceutical dosage form as defined in  claim 30 , wherein said ratio of ethylcellulose to enteric polymer is from about 2:1 to about 1:2. 
     
     
         32 . A pharmaceutical dosage form as defined in  claim 31 , wherein said enteric polymer is hydroxypropyl methylcellulose phthalate. 
     
     
         33 . A pharmaceutical dosage form as defined in  claim 32 , wherein said ratio is about 1:1. 
     
     
         34 . A dosage form as defined in  claim 22 , wherein said IR beads release substantially all of the nizatidine contained therein within the first hour after administration of the dosage form. 
     
     
         35 . A pharmaceutical dosage form as defined in  claim 22 , wherein said IR beads and TPR beads are present in a ratio from about 3:1 to about 1:3. 
     
     
         36 . A pharmaceutical dosage form as defined in  claim 35 , wherein said IR beads and TPR beads are present in a ratio from about 2:1 to about 1:2. 
     
     
         37 . A pharmaceutical dosage form as defined in  claim 22 , wherein the total weight of the coating on the TPR beads is about 10-60 weight % based on the total weight of the TPR beads. 
     
     
         38 . A pharmaceutical dosage form as defined in  claim 22 , wherein said IR beads contain a total of about 50-100 mg of nizatidine and said TPR beads contain a total of about 50-100 mg of nizatidine. 
     
     
         39 . A method for the preparation of the dosage form of  claim 1 , comprising the steps of:
 a. preparing a nizatidine-containing core to form IR beads;   b. coating a fraction of the IR beads with a mixture of plasticized ethylcellulose and an enteric polymer to form TPR beads; and   c. filling capsules with IR beads and TPR beads at a ratio from about 3:1 to about 1:3.   
     
     
         40 . The method of  claim 39 , wherein said nizatidine-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. 
     
     
         41 . The method of  claim 39 , wherein said nizatidine-containing core is produced by granulating and milling and/or by extruding and spheronizing a polymer composition containing nizatidine. 
     
     
         42 . A method of providing a subject with a timed, sustained release dosage of nizatidine which comprises orally administering to said subject a dosage form of  claim 22 . 
     
     
         43 . The method according to  claim 42 , wherein said dosage form is administered two times a day. 
     
     
         44 . The method according to  claim 43 , wherein said dosage form is administered once in the evening and once in the morning. 
     
     
         45 . A method of treating a human having a gastro-intestinal disorder, comprising administering to the human a pulsatile release pharmaceutical dosage form comprising a therapeutically effective amount of a histamine H 2  antagonist. 
     
     
         46 . The method of  claim 45 , wherein the histamine H 2  antagonist is selected from the group consisting of nizatidine, cimetidine, ranitidine and famotidine. 
     
     
         47 . The method of  claim 46 , wherein the histamine H 2  antagonist is nizatidine. 
     
     
         48 . The method of  claim 45 , wherein the pulsatile release pharmaceutical dosage form is bi-modal. 
     
     
         49 . The method of  claim 45 , wherein the gastro-intestinal disorder is an acid peptic disease. 
     
     
         50 . The method of  claim 49 , wherein the acid peptic disease is selected from the group consisting of Gastroesophogeal Reflux Disease (GERD), ulcers, heartburn, Nocturnal Acid Breakthrough, nighttime heartburn, regurgitation and retrosternal pain. 
     
     
         51 . The method of  claim 45 , wherein about 100 mg to about 400 mg of a histamine H 2  antagonist is administered. 
     
     
         52 . The method of  claim 45 , wherein the human is diabetic. 
     
     
         53 . A method of treating a human having a gastro-intestinal disorder, comprising administering to the human once daily a bi-modal pulsatile release oral pharmaceutical dosage form comprising:
 immediate release (IR) beads comprising a core particle containing nizatidine;   timed pulsatile release (TPR) beads, wherein said TPR beads comprise:
 a core particle containing nizatidine; and 
 a pulse coating surrounding said core. 
   
     
     
         54 . The method of  claim 53 , wherein about 150 mg to about 300 mg of nizatidine is administered. 
     
     
         55 . A method of administering nizatidine, comprising administering orally to a human a bi-modal pulsatile release formulation comprising nizatidine that provides two peak blood plasma concentrations of nizatidine occurring from about 2.0 to about 4.0 hours apart, wherein the first peak concentration occurs within 2 hours after administration and wherein a therapeutic level of nizatidine is maintained for about 6 to about 8 hours after administration. 
     
     
         56 . The method of  claim 55 , wherein the formulation is administered in the evening. 
     
     
         57 . The method of  claim 55 , wherein the formulation is administered in the morning. 
     
     
         58 . The method of  claim 55 , wherein about 150 mg to about 300 mg of nizatidine is administered. 
     
     
         59 . The method of  claim 55 , wherein the formulation is administered once a day. 
     
     
         60 . The method of  claim 55 , wherein the formulation is administered twice a day. 
     
     
         61 . The method of  claim 55 , wherein about 150 mg of nizatidine is administered and the first peak concentration is from about 200 to about 800 ng/ml. 
     
     
         62 . The method of  claim 55 , wherein about 150 mg of nizatidine is administered and the second peak concentration is from about 200 to about 800 ng/ml. 
     
     
         63 . The method of  claim 55 , wherein about 300 mg of nizatidine is administered and the first peak concentration is from about 400 to about 1000 ng/ml. 
     
     
         64 . The method of  claim 55 , wherein about 300 mg of nizatidine is administered and the second peak concentration is from about 600 to about 1200 ng/ml. 
     
     
         65 . The method of  claim 55 , wherein the formulation comprises:
 immediate release (IR) beads comprising a core particle containing nizatidine;   timed pulsatile release (TPR) beads, wherein said TPR beads comprise:
 a core particle containing nizatidine; and 
 a pulse coating surrounding said core. 
   
     
     
         66 . A method of administering nizatidine, comprising administering orally to a human a bi-modal pulsatile release formulation producing a first peak blood plasma concentration and a second peak blood level concentration, wherein the ratio of the first peak to the second peak is between about 75:25 and about 25:75. 
     
     
         67 . The method of  claim 66 , wherein the ratio is between about 67:33 and about 33:67. 
     
     
         68 . The method of  claim 66 , wherein the formulation comprises:
 immediate release (IR) beads comprising a core particle containing nizatidine;   timed pulsatile release (TPR) beads, wherein said TPR beads comprise:
 a core particle containing nizatidine; and 
 a pulse coating surrounding said core. 
   
     
     
         69 . The method of  claim 66 , wherein the formulation is administered in the evening. 
     
     
         70 . The method of  claim 66 , wherein the formulation is administered in the morning. 
     
     
         71 . The method of  claim 66 , wherein about 150 mg to about 300 mg of nizatidine is administered. 
     
     
         72 . The method of  claim 66 , wherein the formulation is administered once a day. 
     
     
         73 . The method of  claim 66 , wherein the formulation is administered twice a day. 
     
     
         74 . The method of  claim 66 , wherein about 150 mg of nizatidine is administered and the first peak concentration is from about 200 to about 800 ng/ml. 
     
     
         75 . The method of  claim 66 , wherein about 150 mg of nizatidine is administered and the second peak concentration is from about 200 to about 800 ng/ml. 
     
     
         76 . The method of  claim 66 , wherein about 300 mg of nizatidine is administered and the first peak concentration is from about 400 to about 1000 ng/ml. 
     
     
         77 . The method of  claim 66 , wherein about 300 mg of nizatidine is administered and the second peak concentration is from about 600 to about 1200 ng/ml. 
     
     
         78 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of a single one of said dosage forms in an adult human produces a blood plasma concentration of nizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first eight hours shown in  FIG. 7 . 
     
     
         79 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of a single one of said dosage forms in an adult human produces a blood plasma concentration of nizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first eight hours shown in  FIG. 8 . 
     
     
         80 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of a single one of said dosage forms twice daily in an adult human produces a blood plasma concentration of nizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first twenty four hours shown in FIG. 
     
     
         81 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of two of said dosage forms once daily in an adult human produces a blood plasma concentration of nizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first eight hours shown in  FIG. 9 . 
     
     
         82 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of a single one of said dosage forms in an adult human produces a blood plasma concentration of nizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first eight hours shown in any one of  FIGS. 10-55 . 
     
     
         83 . An extended release (ER) oral dosage form comprising 150 mg of nizatidine, which after oral administration of a single one of said dosage forms in an adult human produces a blood plasma concentration of n-desmethylnizatidine ranging from 80 to 120% of the blood plasma concentration values per time period over the first eight hours shown in any one of  FIGS. 56-101 . 
     
     
         84 . The method of  claim 55 , wherein the first peak concentration occurs within 1 hour after administration.