	US 12,128,140 B2
	Extended release pharmaceutical formulation
Paul William Glue, Dunedin (NZ); Natalie June Medlicott, Dunedin (NZ); and Peter William Surman, Auckland (NZ)
Assigned to Douglas Pharmaceuticals, Ltd., Lincoln (NZ)
Appl. No. 17/442,239
Filed by DOUGLAS PHARMACEUTICALS LTD., Auckland (NZ)
PCT Filed Mar. 5, 2020, PCT No. PCT/IB2020/051909 § 371(c)(1), (2) Date Sep. 23, 2021, PCT Pub. No. WO2020/194087, PCT Pub. Date Oct. 1, 2020.
Application 17/442,239 is a continuation of application No. 16/362,848, filed on Mar. 25, 2019, granted, now 10,869,838, issued on Dec. 22, 2020.
Application 16/362,848 is a continuation in part of application No. 15/728,695, filed on Oct. 10, 2017, granted, now 10,441,544, issued on Oct. 15, 2019.
Prior Publication US 2022/0183983 A1, Jun. 16, 2022
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 9/28 (2006.01); A61K 9/00 (2006.01); A61K 9/20 (2006.01); A61K 31/135 (2006.01); A61K 45/06 (2006.01); A61P 25/22 (2006.01); A61P 25/24 (2006.01)

CPC A61K 9/2031 (2013.01) [A61K 9/0053 (2013.01); A61K 9/2013 (2013.01); A61K 9/2813 (2013.01); A61K 9/2853 (2013.01); A61K 9/2866 (2013.01); A61K 31/135 (2013.01); A61K 45/06 (2013.01); A61P 25/22 (2018.01); A61P 25/24 (2018.01); A61K 9/2095 (2013.01)]

66 Claims

1. A method of treating a patient for a condition selected from the group consisting of treatment-resistant depression; and treatment-resistant anxiety, including but not limited to DSM-V Generalized Anxiety Disorder, Social Anxiety Disorder, Panic Disorder, Post-Traumatic Stress Disorder and/or Obsessive-Compulsive Disorder, comprising:

selecting a patient in need of such treatment; and

orally administering to the patient a solid, oral, extended release pharmaceutical tablet comprising:

(A) a core comprising:

i) a therapeutically effective amount of an active agent selected from the group consisting of ketamine, norketamine, pharmaceutically acceptable salts thereof, and combinations thereof;

ii) at least one high molecular weight polyethylene oxide (PEO) that is cured, wherein said high molecular weight PEO has an approximate molecular weight of from 2 million to 7 million, based upon rheological measurements, and is present in an amount of at least about 30%(by weight) of the core;

(B) a coating on said core, wherein said tablet is crush resistant and has a breaking strength of at least about 200 N; and

wherein when said tablet is administered to a patient said tablet provides a pharmacokinetic parameter selected from the group consisting of:

after administration of a single dose of 60 mg ketamine a mean ketamine Cmax of about 10 ng/ml or a ketamine Cmax between about 5 and about 15 ng/ml;

after administration of a single dose of 120 mg ketamine a mean ketamine Cmax of about 16 ng/mL or a ketamine Cmax between about 7 and about 32 ng/ml;

after administration of a single dose of 240 mg ketamine a mean ketamine Cmax of about 38 ng/ml or a ketamine Cmax between about 19 and about 47 ng/ml;

after administration of a single dose of 60 mg of the active agent a mean norketamine Cmax of about 74 ng/ml or a norketamine Cmax between about 59 and about 91 ng/ml;

after administration of a single dose of 120 mg of the active agent a mean norketamine Cmax of about 161 ng/mL or a norketamine Cmax between about 90 and about 250 ng/ml;

after administration of a single dose of 240 mg of the active agent a mean norketamine Cmax of about 315 ng/ml or a norketamine Cmax between about 222 and about 394 ng/ml;

after administration of a single dose of 60 mg ketamine a mean ketamine AUC 0-∞ of about 79 ng.h/mL or a ketamine AUC 0-∞ between about 36 and about 135 ng.h/mL;

after administration of a single dose of 120 mg ketamine a mean ketamine AUC 0-∞ of about 197 ng.h/mL or a ketamine AUC 0-∞ between about 93 and about 460 ng.h/mL;

after administration of a single dose of 240 mg ketamine a mean ketamine AUC 0-∞ of about 389 ng.h/mL or a ketamine AUC 0-∞ between about 231 and about 521 ng.h/mL;

after administration of a single dose of 60 mg of the active agent a mean norketamine AUC 0-∞ of about 872 ng.h/mL or a norketamine AUC 0-∞ between about 549 and about 1543 ng.h/mL;

after administration of a single dose of 120 mg of the active agent a mean norketamine AUC 0-0 of about 2133 ng.h/mL or a norketamine AUC 0-∞ between about 1353 and about 3260 ng.h/mL;

after administration of a single dose of 240 mg of the active agent a mean norketamine AUC 0-∞ of about 4087 ng.h/mL or a norketamine AUC 0-∞ between about 3205 and about 5216 ng.h/mL;

after administration of 5 doses of 60 mg ketamine administered every 12 hours a mean ketamine Cmax of about 12 ng/ml or a ketamine Cmax between about 8 and about 23 ng/ml;

after administration of 5 doses of 120 mg ketamine administered every 12 hours a mean ketamine Cmax of about 21 ng/mL or a ketamine Cmax between about 7 and about 45 ng/ml;

after administration of 5 doses of 240 mg ketamine administered every 12 hours a mean ketamine Cmax of about 42 ng/mL or a ketamine Cmax between about 33 and about 53 ng/ml;

after administration of 5 doses of 60 mg of the active agent administered every 12 hours a mean norketamine Cmax of about 125 ng/mL or a norketamine Cmax between about 85 and about 185 ng/mL;

after administration of 5 doses of 120 mg of the active agent administered every 12 hours a mean norketamine Cmax of about 230 ng/ml or a norketamine Cmax between about 168 and about 335 ng/ml;

after administration of 5 doses of 240 mg of the active agent administered every 12 hours a mean norketamine Cmax of about 421 ng/ml or a norketamine Cmax between about 363 and about 474 ng/ml;

after administration of 5 doses of 60 mg ketamine administered every 12 hours a mean ketamine AUC 0-12 of about 74 ng.h/mL or a ketamine AUC 0-12 between about 35 and about 156 ng.h/mL;

after administration of 5 doses of 120 mg ketamine administered every 12 hours a mean ketamine AUC 0-12 of about 133 ng.h/mL or a ketamine AUC 0-12 between about 58 and about 287 ng.h/mL;

after administration of 5 doses of 240 mg ketamine administered every 12 hours a mean ketamine AUC 0-12 of about 221 ng.h/mL or a ketamine AUC 0-12 between about 145 and about 328 ng.h/mL;

after administration of 5 doses of 60 mg of the active agent administered every 12 hours a mean norketamine AUC 0-12 of about 981 ng.h/mL or a norketamine AUC 0-12 between about 608 and about 1583 ng.h/mL;

after administration of 5 doses of 120 mg of the active agent administered every 12 hours a mean norketamine AUC 0-12 of about 1697 ng.h/mL or a norketamine AUC 0-12 between about 1124 and about 2557 ng.h/mL;

after administration of 5 doses of 240 mg of the active agent administered every 12 hours a mean norketamine AUC 0-12 of about 3025 ng.h/mL or a norketamine AUC 0-12 between about 2381 and about 3666 ng.h/mL;

a mean t_maxof said active agent between about 1.5 and about 3.5 hours after administration of a single dose of 60 mg or 120 mg or 240 mg;

a mean t_maxof said active agent between about 1.5 and about 3.5 hours after administration of 5 doses of 60 mg administered every 12 hours;

a mean t_maxof said active agent between about 1.5 and about 3.5 hours after administration of 5 doses of 120 mg administered every 12 hours;

a mean t_maxof said active agent between about 1.5 and about 3.5 hours after administration of 5 doses of 240 mg administered every 12 hours;

a ratio of norketamine Cmax: ketamine Cmax of between about 4 to about 15 when said tablet is administered at a single dose of about 60 mg to a patient; and

a ratio of norketamine AUC:ketamine AUC of between about 7 to about 15 when said tablet is administered at a single dose of about 60 mg to a patient, wherein the tablet treats the symptoms of said treatment-resistant depression or said treatment-resistant anxiety.