Controlled release hydrocodone formulations

A twice-a-day solid controlled-release oral dosage form, the dosage form comprising

• a controlled-release matrix comprising
• (i) hydrocodone bitartrate in an amount from about 0.5 mg to about 1250 mg of hydrocodone and
• (ii) an effective amount of a controlled release material to render the dosage form suitable for twice-a-day administration, wherein the controlled release material is selected from the group consisting of
• a mixture of (a) a copolymer of acrylic and methacrylic ester with a molar ratio of ammonium groups to neutral (meth)acrylic esters of 1:20, (b) a copolymer of acrylic and methacrylic ester with a molar ratio of ammonium groups to neutral (meth)acrylic esters of 1:40, and (c) stearyl alcohol;
• a mixture of (a) a copolymer of acrylic and methacrylic ester with a molar ratio of ammonium groups to neutral (meth)acrylic esters of 1:40, (b) triacetin and (c) stearyl alcohol;
• and
• a mixture of (a) microcrystalline cellulose, (b) stearyl alcohol, and (c) glyceryl behenate,
• said dosage form providing an in-vitro release of from 18% to about 42.5% by weight of the 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 900 ml of Simulated Intestinal Fluid (SIF) without enzyme,
• from about 25 to about 65% by weight of the hydrocodone after 2 hours, from about 45 to about 85% by weight of the hydrocodone after 4 hours, and greater than about 60% by weight of the hydrocodone after 8 hours, when measured by the USP Basket method at 100 rpm in 900 ml aqueous buffer at a pH of 1.2 at 37° C.;
• and
• after a first administration to a human patient,
• a therapeutic effect for about 12 hours,
• a flat plasma concentration profile of hydrocodone such that a plasma concentration of hydrocodone after attaining a maximum plasma concentration during the dosing interval stays within from about 60 to about 100% of the maximum plasma concentration for the remainder of the dosing interval,
• a plasma concentration of hydrocodone of at least 8 ng/ml at from about 2 to about 8 hours after administration and of at least 6 ng/ml at about 12 hours after administration, based on oral administration of the dosage form containing 15 mg hydrocodone bitartrate,
• a rate of absorption during the time period from Tmax to about 12 hours after oral administration of the dosage form which is from about 60% to about 100% of the rate of elimination during the same time period, and
• a Cmax of hydrocodone which is less than 50% of the Cmax of an equivalent dose of an immediate release hydrocodone reference formulation.