# US 9,433,619 B1 · Treating pain in patients with hepatic impairment > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,433,619 B1 - Document ID: US9433619B1 - Status: Granted - Kind: B1 - Application number: 15/154,527 - Filed: 2016-05-13 - Published: 2016-09-08 - Granted: 2016-09-06 - Earliest claimed: 2012-07-31 - Assignees: Pemix Ireland Pain Limited - Applicants: Pernix Ireland Pain Limited - Inventors: Andrew Hartman; Christopher M. Rubino; Cynthia Y. Robinson - Web page: https://patentgrep.com/patent/US9433619B1 ## CPC - A61K 31/485: Morphinan derivatives, e.g. morphine, codeine - A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration} - A61K 9/1676: {having a drug-free core with discrete complete coating layer containing drug (adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921)} - A61K 9/4808: {characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release (capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084)} - A61K 9/485: {Inorganic compounds} - A61K 9/4858: {Organic compounds} - A61K 9/4866: {Organic macromolecular compounds} - A61K 9/50: Microcapsules {having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals (A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167)} - A61K 9/5026: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates} - A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose} - A61K 9/5078: {with drug-free core} - A61K 9/5084: {Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs (tablets containing such a mixture A61K9/2077)} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract An extended release composition for an analgesic active pharmaceutical ingredient which may be an opioid, preferably hydrocodone as the only active ingredient. The extended release composition preferably comprises a extended release composition which may be in the form of beads contained in an oral dosage form such as gelatin capsules. The composition is designed to release hydrocodone in a way such that the increase in hydrocodone exposure in hepatically impaired patients is not clinically significant. The oral dosage units are supplied as part of a kit, which also includes a primary package and a package insert all sold as a commercially marketed product. The primary package and package insert are contained in an optional secondary package and the package insert does not contain a warning, a dosing instruction, or a dosing table specifically directed to patients suffering from mild, moderate or severe hepatic impairment, and preferably explicitly states that dosing adjustment is not required for mild or moderate hepatic impairment. ## Claims ### Claim 1 A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising: administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient; wherein the dosage unit comprises a first formulation of hydrocodone bitartrate and a second formulation of hydrocodone bitartrate, wherein the dosage unit provides a release profile of hydrocodone such that: (1) the average hydrocodone AUC0-inf per 20 mg of hydrocodone bitartrate dosed to subjects not suffering from renal or hepatic impairment is in the range of about 300 ng*h/mL to about 500 ng*h/mL; (2) the average hydrocodone AUC0-inf per 20 mg of hydrocodone bitartrate dosed to subjects suffering from mild hepatic impairment is in the range of about 300 ng*h/mL to about 570 ng*h/mL; and (3) the average hydrocodone AUC0-inf per 20 mg of hydrocodone bitartrate dosed to subjects suffering from moderate hepatic impairment is in the range of about 300 ng*h/mL to about 700 ng*h/mL. ### Claim 2 (depends on 1) The method of claim 1, wherein the dosage unit provides a plasma half-life of hydrocodone of about 8 hours in patients without hepatic impairment. ### Claim 3 (depends on 1) The method of claim 1, wherein the dosage unit provides a plasma half-life of hydrocodone of about 9 hours in patients with mild hepatic impairment. ### Claim 4 (depends on 1) The method of claim 1, wherein the dosage unit provides a plasma half-life of hydrocodone of about 10 hours in patients with moderate hepatic impairment. ### Claim 5 (depends on 1) The method of claim 1, wherein the first formulation comprises an immediate release component and the second formulation comprises a sustained release component. ### Claim 6 (depends on 5) The method of claim 5, wherein the immediate release component comprises a first population of particles and the sustained release component comprises a second population of particles. ### Claim 7 (depends on 1) The method of claim 1, wherein the first formulation comprises 15 to 25 percent by weight of the total hydrocodone in the oral dosage unit and the second formulation comprises 75 to 85 percent by weight of the total hydrocodone in the oral dosage unit. ### Claim 8 (depends on 1) The method of claim 1, wherein the dosage unit is formulated to release about 10% to about 30% of the hydrocodone in a first hour and release more than about 60% of the hydrocodone during a first 12 hours after placement in a USP dissolution apparatus buffered at a pH of 6. ### Claim 9 A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising: administering to the patient having mild or moderate hepatic impairment an oral dosage unit having at least 20 mg of hydrocodone bitartrate as the only active ingredient, wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate. ### Claim 10 (depends on 9) The method of claim 9, wherein the dosage unit comprises a multiparticulate modified release composition. ### Claim 11 (depends on 10) The method of claim 10, wherein the dosage unit comprises a capsule containing the multiparticulate modified release composition. ### Claim 12 (depends on 11) The method of claim 11, wherein the multiparticulate modified release composition comprises a first population of beads containing 15 to 25% by weight of the total hydrocodone in the oral dosage unit as an immediate release population, and a second population of beads containing 75 to 85 percent by weight of the total hydrocodone in the oral dosage unit as a sustained release population. ### Claim 13 (depends on 12) The method of claim 12, wherein the multiparticulate modified release composition comprises a third population of beads which are different from beads in the first and second populations of beads. ### Claim 14 (depends on 12) The method of claim 12, wherein the second population of beads comprises a polymer coating comprising one or more of cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, ammonio methacrylate copolymers, polyacrylic acid, polyacrylate and methacrylate copolymers, polyvinyl acetaldiethylamino acetate, hydroxypropyl methylcellulose acetate succinate and shellac. ### Claim 15 (depends on 14) The method of claim 14, wherein the polymer coating comprises ammonio methacrylate copolymers. ### Claim 16 (depends on 15) The method of claim 15, wherein the first population of beads and the second population of beads comprise sugar spheres as an inert core. ### Claim 17 (depends on 9) The method of claim 9, wherein the oral dosage unit contains 20 mg, 30 mg, 40 mg or 50 mg of hydrocodone bitartrate. ### Claim 18 A method of treating pain in a patient having mild or moderate hepatic impairment, the method comprising: administering to the patient having mild or moderate hepatic impairment an oral dosage unit having hydrocodone bitartrate as the only active ingredient; wherein the dosage unit comprises an extended release formulation of hydrocodone bitartrate; wherein the dosage unit is formulated to release about 10% to about 30% of the hydrocodone in a first hour and release more than about 60 of the hydrocodone during a first 12 hours after placement in a USP dissolution apparatus buffered at a pH of 6.8; wherein the dosage unit provides a release profile of hydrocodone such that the average hydrocodone AUC0-inf per 20 mg of hydrocodone bitartrate dosed to subjects not suffering from renal or hepatic impairment is in the range of about 312 ng*h/mL to about 500 ng*h/mL; and wherein the dosage unit provides a release profile of hydrocodone such that the average hydrocodone Cmax per 20 mg of hydrocodone bitartrate dosed to subjects not suffering from renal or hepatic impairment is in the range of about 17 ng/mL to about 27 ng/mL. ### Claim 19 (depends on 18) The method of claim 18, wherein the dosage unit comprises at least 20 mg of hydrocodone bitartrate. ### Claim 20 (depends on 19) The method of claim 19, wherein the dosage unit contains 20 mg, 30 mg, 40 mg or 50 mg of hydrocodone bitartrate.