Extended release pharmaceutical formulation
The invention provides an oral extended release formulation for the treatment of treatment-resistant depression and treatment-resistant anxiety.
1. 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, pharmaceutically acceptable salts thereof, and combinations thereof, wherein the active agent is present at a concentration of at least about 12% ketamine base w/w of the core;
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 about 7 million, based upon rheological measurements, and is present in an amount of at least 75% (by weight) of the core; and
iii) magnesium stearate is present at a concentration of about 1% to about 3% by weight;
(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 said tablet provides a pharmacokinetic parameter selected from the group consisting of: a mean ketamine Cmax of about 10 ng/mL after administration of a single dose of 60 mg to a patient; a mean ketamine Cmax of about 16 ng/mL after administration of a single dose of 120 mg to a patient; a mean ketamine Cmax of about 38 ng/mL after administration of a single dose of 240 mg;
a mean ketamine AUC 0-∞ of about 79 ng·h/mL after administration of a single dose of 60 mg; a mean ketamine AUC 0-∞ of about 197 ng·h/mL after administration of a single dose of 120 mg to a patient; a mean ketamine AUC 0-∞ of about 385 ng·h/mL after administration of a single dose of 240 mg.
2. The tablet of claim 1 wherein the dosage amount of active agent is selected from the group consisting of about 30 mg, about 60 mg, about 120 mg, and about 240 mg.
3. The tablet of claim 1 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.
4. The tablet of claim 1 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.
5. The tablet of claim 1 wherein the tablet is suitable for once daily administration or twice-daily administration to a subject.
6. The tablet of claim 1 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.
7. 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, pharmaceutically acceptable salts thereof, and combinations thereof, wherein the active agent is present at a concentration of at least about 12% ketamine base w/w of the core;
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 about 7 million, based upon rheological measurements, and is present in an amount of at least 75% (by weight) of the core; and
iii) magnesium stearate is present at a concentration of about 1% to about 3% by weight;
(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 said tablet provides a pharmacokinetic parameter selected from the group consisting of: a mean ketamine Cmax of about 12 ng/mL after administration of 5 doses of 60 mg administered every 12 hours to a patient; a mean ketamine Cmax of about 21 ng/mL after administration of 5 doses of 120 mg administered every 12 hours to a patient; a mean ketamine Cmax of about 42 ng/mL after administration of 5 doses of 240 mg administered every 12 hours to a patient;
a mean ketamine AUC 0-12 of about 74 ng·h/mL after administration of 5 doses of 60 mg administered every 12 hours to a patient; a mean ketamine AUC 0-12 of about 133 ng·h/mL after administration of 5 doses of 120 mg administered every 12 hours to a patient; a mean ketamine AUC 0-12 of about 217 ng·h/mL after administration of 5 doses of 240 mg administered every 12 hours to a patient.
8. The tablet of claim 7 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.
9. The tablet of claim 7 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.
10. The tablet of claim 7 wherein the tablet is suitable for once daily administration or twice-daily administration to a subject.
11. The tablet of claim 7 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.