Extended release dosage forms of pregabalin

Abstract

The present invention relates to extended-release pharmaceutical compositions comprising pregabalin or a salt thereof, which are adapted to release the pregabalin active ingredient according to a dual release profile. The formulations comprise two components, the first (fast ER) providing extended-release of the active ingredient in a short controlled manner lasting from about 4 to about 6 hours, and the second (slow ER or maintenance) providing extended release of the active ingredient over a period of 24 hours. The proportion of each component in the formulation may be adjusted to achieve the desired AUC and therapeutic effect following oral administration to a subject. The invention further relates to methods of using the pharmaceutical compositions for treating conditions and disorders which are responsive to pregabalin treatment, such as neuropathic pain associated with diabetic peripheral neuropathy (DPN), post herpetic neuralgia (PHN), epilepsy, seizures and fibromyalgia.

1 . An oral, extended-release (ER) pharmaceutical composition comprising as an active ingredient pregabalin or a salt thereof and a pharmaceutically acceptable carrier or excipient, wherein the composition comprises two components each containing pregabalin or a salt thereof comprising a first component that provides pH independent controlled release of the pregabalin active ingredient contained therein over a time period of about 4 to about 6 hours, and a second component that provides pH independent controlled release of the pregabalin active ingredient contained therein over a time period of about 24 hours. 
     
     
         2 . The composition of  claim 1 , wherein the ratio of the first component to the second component is from about 50%:50% (wt/wt) to about 10%:90% (wt/wt). 
     
     
         3 . The composition of  claim 2 , wherein the ratio of the first component to the second component is about 30%:70% (wt/wt) or about 40%:60% (wt/wt). 
     
     
         4 . The composition of  claim 1 , wherein the ratio of the first component to the second component is from about 50%:50% (wt/wt) to about 90%:10% (wt/wt). 
     
     
         5 . The composition of  claim 4 , wherein the ratio of the first component to the second component is from about 30%:70% (wt/wt) or about 40%:60% (wt/wt). 
     
     
         6 . The composition of  claim 1 , wherein the composition is adapted for once-daily administration. 
     
     
         7 . The composition of  claim 1 , wherein the first component and the second component each independently comprises at least one pharmaceutically acceptable excipient selected from the group consisting of a pH-independent release controlling polymer, a binder, a glidant, a plasticizer, a matrix former, a disintegrant, a lubricant, and any combination thereof. 
     
     
         8 . The composition of  claim 7 , wherein the first component and the second component each comprises at least one pH-independent release controlling polymer selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), polyvinylpyrrolidone (PVP), ethyl cellulose (EC), cellulose acetate, acrylic polymers, and combinations thereof. 
     
     
         9 . The composition of  claim 7 , wherein the pH-independent release controlling polymer is selected from the group consisting of hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), ethyl cellulose (EC), and any combination thereof. 
     
     
         10 . The composition of  claim 7 , wherein the binder is selected from the group consisting of hydroxypropyl cellulose (HPC) and polyvinylpyrrolidone (PVP). 
     
     
         11 . The composition of  claim 7 , wherein the lubricant is selected from the group consisting of magnesium stearate, glyceryl behenate and sodium stearyl fumarate. 
     
     
         12 . The composition of  claim 7  wherein the glidant is silicon dioxide. 
     
     
         13 . The composition of  claim 1 , wherein the first component and the second component each comprise pregabalin, ethyl cellulose, glyceryl behenate and magnesium stearate. 
     
     
         14 . The composition of  claim 13 , wherein the first component is uncoated and wherein the second component further comprises a coating comprising ethyl cellulose. 
     
     
         15 . The composition of  claim 1 , wherein the first component and the second component are each in the form of ER beads or mini-tablets comprising pregabalin, a first pH-independent release controlling polymer, at least one lubricant and/or matrix former, and a coating comprising a second pH-independent release controlling polymer which may be the same or different from the first pH-independent release controlling polymer, wherein the same coating in different amounts, is used for the first and second components. 
     
     
         16 . The composition of  claim 1 , wherein pregabalin in each component is released in a controlled release order selected from the group consisting of zero, first, second and third release order, and any pseudo orders thereof. 
     
     
         17 . The composition of  claim 1 , wherein pregabalin is released from the pharmaceutical composition to provide a lower C max , a smaller index of fluctuation, and/or a reduced side effects profile as compared to a similar dose of an immediate release formulation of pregabalin. 
     
     
         18 . A method of treating a condition or disorder which is responsive to pregabalin treatment, comprising the step of administering to a subject in need thereof an effective amount of the oral, extended-release (ER) pharmaceutical composition of  claim 1 . 
     
     
         19 . The method of  claim 18 , wherein the condition or disorder selected from the group consisting of epilepsy, pain, diabetic peripheral neuropathy, postherpetic neuralgia, physiological condition associated with psychomotor stimulants, inflammation, gastrointestinal damage, alcoholism, insomnia, fibromyalgia, anxiety, depression, mania and bipolar disorder.