Sustained release formulations of lorazepam

Abstract

A pharmaceutical composition for delivering lorazepam in a prolonged fashion is achieved with prolonged release lorazepam pharmaceutical beads. The composition typically contains sustained release lorazepam beads and delayed sustained release lorazepam beads. The composition can provide once daily dosing that maintains 24 hour therapeutic effect under steady state conditions.

1 .- 20 . (canceled) 
     
     
         21 . A pharmaceutical composition comprising (i) lorazepam sustained release beads comprising lorazepam dispersed in a polymer matrix; and (ii) lorazepam delayed sustained release beads comprising (a) a core comprising lorazepam dispersed in a polymer matrix and (b) a delayed release coating surrounding the core, wherein the ratio of the lorazepam sustained release beads to the lorazepam delayed sustained release beads is from 1:0.7 to 1.3, based on the weight of the lorazepam. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the lorazepam sustained release beads and the core of the lorazepam delayed sustained release beads independently comprise 1 to 4% w/w lorazepam. 
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein the composition comprises a total amount of lorazepam of 0.5 to 6 mg. 
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein the composition comprises a total amount of lorazepam of 2 mg. 
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein about half of the lorazepam present is provided in the sustained release beads and about half of the lorazepam present is provided in the delayed sustained release beads. 
     
     
         26 . The pharmaceutical composition of  claim 21 , wherein all of the lorazepam present in the composition is present in the sustained release beads and the delayed sustained release beads. 
     
     
         27 . The pharmaceutical composition of  claim 21 , wherein the polymer matrices of the sustained release beads and the delayed sustained release beads independently comprise one or more polymers selected from the group consisting of hydroxypropylmethylcellulose, polyacrylates, and polyethylene oxides. 
     
     
         28 . The pharmaceutical composition of  claim 27 , wherein the polymer matrices of the sustained release beads and the delayed sustained release beads independently further comprises one or more binders and/or one or more fillers. 
     
     
         29 . The pharmaceutical composition of  claim 27 , wherein the sustained release beads have a dissolution profile in a two media in vitro dissolution test such that from 20 to 70% of the lorazepam is released in 2 hours, wherein the two media in vitro dissolution test is carried out for two hours in a media that comprises 0.1 N HCl and then is carried out in a media that comprises a phosphate buffer and has a pH of 7.4. 
     
     
         30 . The pharmaceutical composition of  claim 21 , wherein the delayed release coating is an enteric coating. 
     
     
         31 . The pharmaceutical composition of  claim 30 , wherein the delayed release coating is designed to release lorazepam at pH 6 or higher. 
     
     
         32 . The pharmaceutical composition of  claim 30 , wherein the delayed release coating is designed to release lorazepam at pH 6.8 or higher. 
     
     
         33 . The pharmaceutical composition of  claim 30 , wherein the delayed release coating is designed to release lorazepam at pH 7 or higher. 
     
     
         34 . The pharmaceutical composition according to  claim 30 , wherein the delayed sustained release beads have a dissolution profile in a two media in vitro dissolution test such that 90% release of the lorazepam occurs after 6 hours, wherein the two media in vitro dissolution test is carried out for two hours in a media that comprises 0.1 N HCl and then is carried out in a media that comprises a phosphate buffer and has a pH of 7.4. 
     
     
         35 . The pharmaceutical composition of  claim 21 , wherein the delayed release coating is a pH-independent delayed release coating. 
     
     
         36 . The pharmaceutical composition of  claim 21 , wherein the delayed release coating is a pH-independent delayed release coating comprising one or more polymers selected from the group consisting of cellulose acetates, cellulose ethers, ethylcellulose, glycerides, substituted methacrylates, polyvinyl acetates, and polyvinylpyrrolidone. 
     
     
         37 . The pharmaceutical composition according to  claim 35 , wherein the delayed sustained release beads have a dissolution profile in a two media in vitro dissolution test such that the release of 90% of the lorazepam occurs after 10 hours, wherein the two media in vitro dissolution test is carried out for two hours in a media that comprises 0.1 N HCl and then is carried out in a media that comprises a phosphate buffer and has a pH of 7.4. 
     
     
         38 . The pharmaceutical composition of  claim 21 , wherein the delayed release coating comprises a polymer and one or more plasticizers and/or one or more anti-tack agents. 
     
     
         39 . The pharmaceutical composition of  claim 21 , wherein the lorazepam sustained release beads and the lorazepam delayed sustained release beads are provided in a capsule or sachet. 
     
     
         40 . A method of treating an anxiety related disorder comprising administering a composition according to  claim 21  to a subject in need thereof. 
     
     
         41 . The method of  claim 40 , wherein the anxiety related disorder is General Anxiety Disorder. 
     
     
         42 . The method of  claim 40 , wherein the composition is administered once per day.