# US 10,869,838 B2 · Extended release pharmaceutical formulation

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- Number: US 10,869,838 B2
- Document ID: US10869838B2
- Status: Granted
- Kind: B2
- Application number: 16/362,848
- Filed: 2019-03-25
- Published: 2019-07-18
- Granted: 2020-12-22
- Earliest claimed: 2017-10-10
- Assignees: Douglas Pharmaceuticals Limited
- Applicants: Douglas Pharmaceuticals Ltd.
- Inventors: Paul William Glue; Natalie June Medlicott
- Web page: https://patentgrep.com/patent/US10869838B2

## CPC

- A61K 9/2031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2813: {Inorganic compounds}
- A61K 9/2853: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61K 9/2095: {Tabletting processes}
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The disclosure provides an oral extended release formulation for the treatment of treatment-resistant depression and treatment-resistant anxiety.

## Claims

### Claim 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, 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 about 2 million to about 7 million, based upon rheological measurements, and is present in an amount of at least about 75% (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 AUC0-∞ 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 AUC0-∞ 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-∞ of about 2133 ng·h/mL or a norketamine AUC0-∞ between about 1353 and about 3260 ng·h/mL; and
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 AUC0-∞ between about 3205 and about 5216 ng·h/mL.

### Claim 2 (depends on 1)

The tablet of claim 1 wherein the molecular weight of said high molecular weight PEO is selected from the group consisting of at least about 4,000,000; at least about 5,000,000; at least about 6,000,000; and at least about 7,000,000.

### Claim 3 (depends on 1)

The tablet of claim 1 wherein the active agent comprises at least about 1% (by weight) of the core.

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 1)

The tablet of claim 1 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.

### Claim 6 (depends on 1)

The tablet of claim 1 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.

### Claim 7 (depends on 1)

The tablet of claim 1 wherein the tablet is suitable for once daily administration or twice-daily administration to a patient.

### Claim 8 (depends on 1)

The tablet of claim 1 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.

### Claim 9

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 about 2 million to about 7 million, based upon rheological measurements, and is present in an amount of at least about 75% (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 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 AUC0-12 of about 1697 ng·h/mL or a norketamine AUC0-12 between about 1124 and about 2557 ng·h/mL; and
after administration of 5 doses of 240 mg of the active agent administered every 12 hours a mean norketamine AUC0-12 of about 3025 ng·h/mL or a norketamine AUC0-12 between about 2381 and about 3666 ng·h/mL.

### Claim 10 (depends on 9)

The tablet of claim 9 wherein the molecular weight of said high molecular weight PEO is selected from the group consisting of at least about 4,000,000; at least about 5,000,000; at least about 6,000,000; and at least about 7,000,000.

### Claim 11 (depends on 9)

The tablet of claim 9 wherein the active agent comprises at least about 1% (by weight) of the core.

### Claim 12 (depends on 9)

The tablet of claim 9 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.

### Claim 13 (depends on 9)

The tablet of claim 9 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.

### Claim 14 (depends on 9)

The tablet of claim 9 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.

### Claim 15 (depends on 9)

The tablet of claim 9 wherein the tablet is suitable for once daily administration or twice-daily administration to a patient.

### Claim 16 (depends on 9)

The tablet of claim 9 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.

### Claim 17

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 about 2 million to about 7 million, based upon rheological measurements, and is present in an amount of at least about 75% (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:
a mean tmax of 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 tmax of 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 tmax of said active agent between about 1.5 and about 3.5 hours after administration of 5 doses of 120 mg administered every 12 hours; and
a mean tmax of said active agent between about 1.5 and about 3.5 hours after administration of 5 doses of 240 mg administered every 12 hours.

### Claim 18 (depends on 17)

The tablet of claim 17 wherein the molecular weight of said high molecular weight PEO is selected from the group consisting of at least about 4,000,000; at least about 5,000,000; at least about 6,000,000; and at least about 7,000,000.

### Claim 19 (depends on 17)

The tablet of claim 17 wherein the active agent comprises at least about 1% (by weight) of the core.

### Claim 20 (depends on 17)

The tablet of claim 17 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.

### Claim 21 (depends on 17)

The tablet of claim 17 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.

### Claim 22 (depends on 17)

The tablet of claim 17 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.

### Claim 23 (depends on 17)

The tablet of claim 17 wherein the tablet is suitable for once daily administration or twice-daily administration to a patient.

### Claim 24 (depends on 17)

The tablet of claim 17 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.

### Claim 25

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 about 2 million to about 7 million, based upon rheological measurements, and is present in an amount of at least about 75% (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 at a single dose of about 60 mg to a patient provides a pharmacokinetic parameter selected from the group consisting of a ratio of norketamine Cmax: ketamine Cmax of between about 4 to about 15; and a ratio of norketamine AUC:ketamine AUC of between about 7 to about 15.

### Claim 26 (depends on 25)

The tablet of claim 25 wherein the molecular weight of said high molecular weight PEO is selected from the group consisting of at least about 4,000,000; at least about 5,000,000; at least about 6,000,000; and at least about 7,000,000.

### Claim 27 (depends on 25)

The tablet of claim 25 wherein the active agent comprises at least about 1% (by weight) of the core.

### Claim 28 (depends on 25)

The tablet of claim 25 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.

### Claim 29 (depends on 25)

The tablet of claim 25 wherein the tablet is cured at a temperature of about 70° C. to about 75° C.

### Claim 30 (depends on 25)

The tablet of claim 25 wherein the coating comprises:
i) hydroxypropylmethylcellulose;
ii) titanium dioxide; and
iii) polyethylene glycol.

### Claim 31 (depends on 25)

The tablet of claim 25 wherein the tablet is suitable for once daily administration or twice-daily administration to a patient.

### Claim 32 (depends on 25)

The tablet of claim 25 wherein the tablet has no or minimal dissociative side effects upon administration to a patient.