Extended release compositions comprising pyridostigmine

Abstract

Extended release pyridostigmine dosage forms, suitable for maintaining stable plasma concentrations with reduced or minimized initial burst release/dose dumping of pyridostigmine, are provided. The dosage forms include matrix tablets, gastroretentive tablets, and pellets, the latter being suitable for dosing in capsules, tablets, and sachets, as well as for sprinkling on foodstuffs. The disclosure also provides methods for improving patient compliance by administering once-a-day extended release pyridostigmine bromide dosage forms that provide a superior controlled drug release.

What is claimed is: 
     
         1 . A gastroretentive dosage form comprising a core and a permeable elastic membrane comprising at least one orifice and surrounding the core,
 wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, and a gas-generating agent,   wherein the permeable elastic membrane comprises at least one water-insoluble permeable polymer in an amount of from about 70 wt % to about 95 wt % of the membrane composition,   wherein the gas generating agent is selected from the group consisting of carbonate salts, bicarbonate salts and mixture thereof,   wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene oxide, carbomer, sodium alginate, and mixtures thereof, and   wherein the permeable polymer allows passage of the pyridostigmine or a pharmaceutically acceptable salt thereof through the polymer.   
     
     
         2 . The dosage form of  claim 1 , wherein the dosage form provides membrane controlled extended release of the pyridostigmine or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The dosage form of  claim 1 , wherein the dosage form further comprises an immediate release layer covering at least a portion of the permeable elastic membrane and comprising pyridostigmine or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The dosage form of  claim 1 , wherein the core comprises about 50 mg to about 400 mg of pyridostigmine bromide. 
     
     
         5 . The dosage form of  claim 1 , wherein the dosage form provides an invitro release of less than about 35 wt % of pyridostigmine or a pharmaceutically acceptable salt thereof, within about 2 hours of dissolution in 900 ml of a dissolution medium comprising 50 mM of pH 4.5 acetate buffer and 100 mM NaCl, measured using USP Apparatus I at 100 rpm and 37° C. 
     
     
         6 . The dosage form of  claim 1 , wherein the dosage form floats in about 40 minutes or less in 200 ml of a dissolution medium comprising 50 mM of pH 4.5 acetate buffer and 100 mM NaCl, measured using Rotating Bottle method at 5 rpm and 37° C., 
     
     
         7 . The dosage form of  claim 1 , wherein the membrane further comprises a plasticizer selected from the group consisting of triethyl citrate, triacetin, polyethylene glycol, propylene glycol, dibutyl sebacate, and mixtures thereof. 
     
     
         8 . The dosage form of  claim 1 , wherein the dosage form is a tablet suitable for once daily administration. 
     
     
         9 . The dosage form of  claim 8 , wherein the once daily administration comprises administration as a single or multiple tablets. 
     
     
         10 . The dosage form of  claim 1 , wherein the swellable water-soluble hydrophilic polymer is hydroxypropyl methylcellulose. 
     
     
         11 . The dosage form of  claim 10 , wherein the hydroxypropyl methylcellulose is present in an amount of from about from about 5 wt % to about 35 wt %, based on the total weight of the core. 
     
     
         12 . The dosage form of  claim 1 , wherein the dosage form provides extended release of pyridostigmine or a pharmaceutically acceptable salt thereof for at least about 12 hours. 
     
     
         13 . The dosage form of  claim 1 , wherein the dosage form exhibits at least 200% volume gain within 60 minutes of coming in contact with 200 ml of a dissolution medium comprising 0.001 N HCL and 10 mM NaCl, measured using Rotating Bottle method, at 5 rpm and 37° C. 
     
     
         14 . The dosage form of  claim 1 , wherein the dosage form, after subjecting to dissolution using a rotating bottle apparatus at 5 rpm and 37° C., in a dissolution medium comprising 0.001N HCl and 10 mM NaCl, followed by compression force testing using TA.XT Plus  apparatus, can withstand a compression force of at least about 10 N until about 14 hours post administration, and can be squeezed even with a compression force less than 5 N at 20 hour post administration into the dissolution medium. 
     
     
         15 . The dosage form of  claim 1 , wherein the dosage form is used for the treatment of postoperative functional bowel bloating. 
     
     
         16 . The dosage form of  claim 1 , wherein the dosage form is used for the treatment of urinary retention. 
     
     
         17 . A method for pretreatment of nerve gas poisoning, the method comprising once-a-day administration to a person in need thereof, a gastroretentive dosage form comprising a core and a permeable elastic membrane comprising at least one orifice and surrounding the core,
 wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, and a gas-generating agent,   wherein the permeable elastic membrane comprises at least one water-insoluble permeable polymer in an amount of from about 70 wt % to about 95 wt % of the membrane composition,   wherein the gas generating agent is selected from the group consisting of carbonate salts, bicarbonate salts and mixture thereof,   wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene oxide, carbomer, sodium alginate, and mixtures thereof, and   wherein the permeable polymer allows passage of the pyridostigmine or a pharmaceutically acceptable salt thereof through the polymer.   
     
     
         18 . The dosage form of  claim 17 , wherein the dosage form provides a membrane controlled extended release of the pyridostigmine or a pharmaceutically acceptable salt thereof. 
     
     
         19 . A method for treatment of myasthenia gravis comprising once-a-day administration to a person in need thereof, a gastroretentive dosage form comprising a core and a permeable elastic membrane comprising at least one orifice and surrounding the core,
 wherein the core comprises pyridostigmine or a pharmaceutically acceptable salt thereof, a swellable water-soluble hydrophilic polymer, and a gas-generating agent,   wherein the permeable elastic membrane comprises at least one water-insoluble permeable polymer in an amount of from about 70 wt % to about 95 wt % of the membrane composition,   wherein the gas generating agent is selected from the group consisting of carbonate salts, bicarbonate salts and mixture thereof,   wherein the swellable water-soluble hydrophilic polymer is selected from the group consisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, polyethylene oxide, carbomer, sodium alginate, and mixtures thereof, and   wherein the permeable polymer allows passage of the pyridostigmine or a pharmaceutically acceptable salt thereof through the polymer.   
     
     
         20 . The dosage form of  claim 19 , wherein the dosage form provides a membrane controlled extended release of the pyridostigmine or a pharmaceutically acceptable salt thereof.