Controlled release hydrocodone formulations

Abstract

A solid oral controlled-release oral dosage form of hydrocodone is disclosed. The dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and a sufficient amount of a controlled release material to render the dosage form suitable for twice-a-day administration to a human patient, the dosage form providing a C 12 /C max ratio of 0.55 to 0.85, said dosage form providing a therapeutic effect for at least about 12 hours.

1 . A solid oral controlled-release dosage form, the dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof and an amount of a controlled release material sufficient to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form, after a first administration to the human patient, providing a C 12 /C max  ratio of 0.55 to 0.85 and a therapeutic effect for about 12 hours. 
     
     
         2 . The dosage form of  claim 1 , wherein said hydrocodone is dispersed in a matrix comprising said controlled release material. 
     
     
         3 . The dosage form of  claim 2 , wherein said matrix is in a multiparticulate form. 
     
     
         4 . The dosage form of  claim 3 , wherein said multiparticulate form comprises multiparticulates compressed into a tablet. 
     
     
         5 . The dosage form of  claim 3 , wherein said multiparticulate form comprises multiparticulates disposed in a pharmaceutically acceptable capsule. 
     
     
         6 . The dosage form of  claim 1 , which provides a C 12 /C max  ratio of 0.65 to 0.75. 
     
     
         7 . The dosage form of  claim 1 , which provides an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone or salt thereof from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C. 
     
     
         8 . The dosage form of  claim 6 , which provides an in-vitro release of from 18% to about 42.5% by weight of the hydrocodone or salt thereof from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C. 
     
     
         9 . The dosage form of  claim 1 , which provides a dissolution rate in-vitro of the hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 at 37° C. from about 25 to about 65% by weight hydrocodone or salt thereof released after 2 hours, from about 45 to about 85% by weight hydrocodone or salt thereof released after 4 hours, and greater than about 60% by weight hydrocodone or salt thereof released after 8 hours. 
     
     
         10 . The dosage form of  claim 1 , which provides a dissolution rate in-vitro of the hydrocodone from the dosage form when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37° C. from about 25 to about 65% by weight hydrocodone or salt thereof released after 2 hours, from about 45 to about 85% by weight hydrocodone or salt thereof released after 4 hours, and greater than about 60% by weight hydrocodone or salt thereof released after 8 hours. 
     
     
         11 . The dosage form of  claim 1 , which provides a T max  of hydrocodone in said patient at from about 2 to about 8 hours after oral administration of the dosage form. 
     
     
         12 . The dosage form of  claim 1 , which provides a T max  of hydrocodone in said patient at from about 3 to about 7 hours after oral administration of the dosage form. 
     
     
         13 . The dosage form of  claim 1 , which provides a T max  of hydrocodone in said patient at from about 4 to about 6 hours after oral administration of the dosage form. 
     
     
         14 . The dosage form of  claim 1 , which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and provides a plasma concentration of hydrocodone of at least 6 ng/ml at about 12 hours after administration, based on oral administration of a dosage form containing 15 mg hydrocodone bitartrate. 
     
     
         15 . The dosage form of  claim 14 , which provides a plasma concentration of hydrocodone of at least 8 ng/ml at from about 3 to about 7 hours after administration. 
     
     
         16 - 22 . (canceled) 
     
     
         23 . The dosage form of  claim 1 , which maintains a plasma concentration of hydrocodone within 80% of C max  for about 1 to about 9 hours during the 12 hour dosing interval. 
     
     
         24 . The dosage form of  claim 1 , which maintains a plasma concentration of hydrocodone within 80% of C max  for about 4 to about 8 hours during the 12 hour dosing interval. 
     
     
         25 . The dosage form of  claim 1 , which maintains a plasma concentration of hydrocodone within 90% of C max  for about 1 to about 6.5 hours during the 12 hour dosing interval. 
     
     
         26 . The dosage form of  claim 1 , which maintains a plasma concentration of hydrocodone within 90% of C max  for about 2 to about 5 hours during the 12 hour dosing interval. 
     
     
         27 - 31 . (canceled) 
     
     
         32 . A solid oral controlled-release dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof together with an amount of a controlled release material sufficient to render said dosage form suitable for twice-a-day administration to a patient population, said dosage form, after a first administration to the patient population, providing a mean T max  of hydrocodone in-vivo at from about 2 to about 8 hours, and providing a mean C 12 /C max  ratio of 0.55 to 0.85, said dosage form providing a therapeutic effect for about 12 hours. 
     
     
         33 - 38 . (canceled) 
     
     
         39 . A solid oral controlled-release oral dosage form, the dosage form comprising an analgesically effective amount of a bitartrate salt of hydrocodone and an amount of a controlled release material sufficient to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form providing an in-vitro release of at least 18% to about 42.5% by weight of the bitartrate salt of hydrocodone from the dosage form at one hour when measured by the USP Basket Method at 100 rpm in 700 ml of Simulated Gastric Fluid (SGF) for 55 minutes at 37° C. and thereafter switching to 900 ml of Simulated Intestinal Fluid (SIF) at 37° C. 
     
     
         40 . (canceled) 
     
     
         41 . A solid oral controlled-release dosage form, the dosage form comprising an analgesically effective amount of hydrocodone or a pharmaceutically acceptable salt thereof, and an amount of a controlled release material sufficient to render said dosage form suitable for twice-a-day administration to a human patient, said dosage form providing a dissolution rate in-vitro of the hydrocodone from the dosage form when measured by the USP Paddle or basket method at 100 rpm in 900 ml aqueous buffer at a pH of 7.5 at 37° C., such that from about 25 to about 65% by weight hydrocodone or salt thereof is released after 2 hours, from about 45 to about 85% by weight hydrocodone or salt thereof is released after 4 hours, and greater than about 60% by weight hydrocodone or salt thereof is released after 8 hours. 
     
     
         42 . The dosage form of  claim 1 , wherein at least some of the hydrocodone or the pharmaceutically acceptable salt thereof is coated over inert pharmaceutically acceptable beads and overcoated with an alkylcellulose, an acrylic polymer, or a mixture thereof. 
     
     
         43 . The dosage form of  claim 1 , wherein the dosage form comprises a plurality of spheroids contained within a gelatin capsule, the spheroids comprising the hydrocodone or pharmaceutically acceptable salt thereof and the controlled release material. 
     
     
         44 . The dosage form of  claim 43 , wherein the spheroids are in a form of spherical granules having a diameter of between 0.1 mm and 2.5 mm. 
     
     
         45 . The dosage form of  claim 44 , wherein the spherical granules have a diameter of between 0.5 mm and 2 mm. 
     
     
         46 . The dosage form of  claim 45 , wherein a portion of the granules provides a controlled release of the hydrocodone or pharmaceutically acceptable salt thereof and a portion of the granules provides an immediate release of the hydrocodone or pharmaceutically acceptable salt thereof. 
     
     
         47 . The dosage form of  claim 46 , wherein the granules providing controlled release of the hydrocodone or pharmaceutically acceptable salt thereof comprise the hydrocodone or pharmaceutically acceptable salt thereof coated with a coating comprising the controlled release material. 
     
     
         48 . The dosage form of  claim 47 , wherein the controlled release material in the coating comprises an acrylic resin. 
     
     
         49 . The dosage form of  claim 1 , which is a coated bead formulation comprising a plurality of inert pharmaceutically acceptable beads coated with the hydrocodone or pharmaceutically acceptable salt thereof and overcoated with an acrylic polymer.