Claims for Patent: 10,322,120

Summary for Patent: 10,322,120

Title:	Treating pain in patients with hepatic impairment
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.
Inventor(s):	Hartman; Andrew (Belmont, CA), Rubino; Christopher M. (Williamsville, NY), Robinson; Cynthia Y. (Burlingame, CA)
Assignee:	Persion Pharmaceuticals LLC (Morristown, NJ)
Application Number:	14/523,162
Patent Claims:	1. A kit for treating pain which requires daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, comprising: a plurality of extended release opioid dosage units; a package holding the dosage units; written instructions for dosing a patient with the dosage units; wherein each dosage unit comprises a capsule comprising: a gelatin capsule shell; excipients comprising sugar spheres, hypromellose, ammonia methacrylate copolymer, silicon dioxide and talc; and an active ingredient consisting essentially only of hydrocodone bitartrate in an amount selected from the group consisting of 15, 20, 30, 40 and 50 mg; wherein each dosage unit comprises a multiparticulate modified release composition including at least two different groups of particles; wherein each dosage unit comprises an immediate release component and a sustained release component; wherein the sustained release component comprises 50% to 90% of the total hydrocodone in each dosage unit; wherein each dosage unit is formulated to release about 10% to about 30% of the hydrocodone in a first hour and releases more than about 60% and less than about 98% of the hydrocodone during a first 12 hours after placement in a USP dissolution apparatus buffered at a pH of 6.8; wherein each dosage unit comprises 5% to 60% by weight hydrocodone bitartrate, 0% to 30% by weight controlled release polymers, and 25% to 95% by weight other excipients; wherein each dosage unit provides a release profile of hydrocodone that does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%, and the release profile of hydrocodone does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 50%; and further wherein the written instructions state that no adjustment in starting dose is required in patients with some degree of hepatic impairment. 2. The kit of claim 1, wherein the degree of hepatic impairment is mild hepatic impairment, and wherein the hydrocodone is formed as hydrocodone bitartrate. 3. The kit of claim 1, wherein the degree of hepatic impairment is moderate hepatic impairment, and wherein the hydrocodone is formed as hydrocodone bitartrate. 4. The kit of claim 1, wherein the amount is selected from the group consisting of 15, 20, and 30 mg; wherein the sustained release component of each dosage unit comprises a controlled release polymer, and comprises 75% to 85% of the total hydrocodone; wherein each dosage unit releases 15% to 25% of the hydrocodone in the first hour; wherein each dosage unit releases 65% to 95% of the hydrocodone during the first 12 hours, wherein the instructions state that no adjustment in starting dose is required for patients with mild hepatic impairment. 5. The kit of claim 4, wherein the amount is selected from the group consisting of 20 or 30 mg; wherein the sustained release component comprises about 80% of the hydrocodone; wherein each dosage unit releases about 21% of the hydrocodone in the first hour; and wherein each dosage unit releases about 85% of the hydrocodone in the first 12 hours, wherein the instructions state that no adjustment in starting dose is required for patients with moderate hepatic impairment. 6. The kit of claim 1, wherein each dosage unit provides a release profile of hydrocodone that does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%, and the release profile of hydrocodone does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%. 7. The kit of claim 1, wherein each dosage unit provides a release profile of hydrocodone that does not increase average hydrocodone C.sub.max in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 9%, and the release profile of hydrocodone does not increase average hydrocodone C.sub.max in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%. 8. The kit of claim 1, wherein each dosage unit provides a release profile of hydrocodone such that: (1) the average hydrocodone AUC.sub.0-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 AUC.sub.0-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 AUC.sub.0-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. 9. The kit of claim 8, wherein each dosage unit provides a release profile of hydrocodone such that the average hydrocodone AUC.sub.0-inf per 20 mg of hydrocodone bitartrate dosed to subjects not suffering from renal or hepatic impairment is in the range of about 317 ng*h/mL to about 465 ng*h/mL. 10. The kit of claim 8, wherein each dosage unit provides a release profile of hydrocodone such that the average hydrocodone AUC.sub.0-inf per 20 mg of hydrocodone bitartrate dosed to subjects suffering from moderate hepatic impairment is in the range of about 352 ng*h/mL to about 666 ng*h/mL. 11. A kit for treating pain which requires daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate, comprising: a plurality of extended release opioid dosage units having hydrocodone bitartrate as the only active ingredient; a package holding the dosage units; wherein each dosage unit comprises a multiparticulate modified release composition including at least two different groups of particles, with at least one group of particles containing an immediate release formulation of hydrocodone bitartrate and at least one group of particles containing a sustained release formulation of hydrocodone bitartrate; wherein each dosage unit comprises a capsule comprising: a gelatin capsule shell; excipients comprising sugar spheres, hypromellose, ammonia methacrylate copolymer, silicon dioxide and talc; and hydrocodone bitartrate; wherein each dosage unit comprises 5% to 60% by weight hydrocodone bitartrate, 0% to 30% by weight controlled release polymers, and 25% to 95% by weight other excipients; wherein each dosage unit provides a release profile of hydrocodone that: (1) does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%; (2) does not increase average hydrocodone AUC.sub.0-inf in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 30%; (3) does not increase average hydrocodone C.sub.max in subjects suffering from mild hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 9%; and (4) does not increase average hydrocodone C.sub.max in subjects suffering from moderate hepatic impairment relative to subjects not suffering from renal or hepatic impairment in an amount of more than 14%. 12. The kit of claim 11, wherein each dosage unit comprises 15 mg or more of hydrocodone bitartrate. 13. The kit of claim 12, wherein each dosage unit comprises 20, 30 or 40 mg of hydrocodone bitartrate. 14. The kit of claim 11, wherein each dosage unit provides a release of about 10% to about 30% of the hydrocodone in a first hour after placement in a USP dissolution apparatus buffered at a pH of 6.8. 15. The kit of claim 11, wherein each dosage unit provides a release of about 60% to about 98% of the hydrocodone during a first 12 hours after placement in a USP dissolution apparatus buffered at a pH of 6.8. 16. The kit of claim 11, wherein each dosage unit provides a release profile of hydrocodone such that: (1) the average hydrocodone AUC.sub.0-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 AUC.sub.0-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 AUC.sub.0-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. 17. The kit of claim 16, wherein each dosage unit provides a release profile of hydrocodone such that the average hydrocodone AUC.sub.0-inf per 20 mg of hydrocodone bitartrate dosed to subjects not suffering from renal or hepatic impairment is in the range of about 317 ng*h/mL to about 465 ng*h/mL. 18. The kit of claim 16, wherein each dosage unit provides a release profile of hydrocodone such that the average hydrocodone AUC.sub.0-inf per 20 mg of hydrocodone bitartrate dosed to subjects suffering from moderate hepatic impairment is in the range of about 352 ng*h/mL to about 666 ng*h/mL. 19. The kit of claim 16, wherein each dosage unit comprises an immediate release component and a sustained release component, and the sustained release component comprises 50% to 90% of the total hydrocodone in each dosage unit.