Abuse-deterrent dosage forms containing esketamine

Patent metadata

Field	Value
Publication number	US-11324707-B2
Application number	US-202016869309-A
Country	US
Kind code	B2
Filing date	May 7, 2020
Priority date	May 7, 2019
Publication date	May 10, 2022
Grant date	May 10, 2022

Abstract

Disclosed herein are immediate release oral dosage forms that contain abuse-deterrent and abuse-resistant features. In particular, the disclosed dosage forms can provide deterrence of abuse by ingestion of multiple individual doses. The disclosed dosage forms can likewise provide protection from overdose in the event of accidental or intentional ingestion of multiple individual doses. The dosage forms may also exhibit abuse resistant properties when physically manipulated, and also when physically manipulated and then administered in a manner not consistent with oral dosing. The dosage forms may also exhibit abuse resistant properties when administered in a manner intended to result in administration of the esketamine in a higher than therapeutic dose.

First claim

What is claimed:

1. An abuse resistant oral dosage form for the administration of esketamine to a subject comprising:
(i) a first population of core-shell particles, each of the core-shell particles of the first population comprising
a core,
an active pharmaceutical layer surrounding the core and comprising esketamine or a pharmaceutically acceptable salt thereof, and
at least one layer surrounding the active pharmaceutical layer, the at least one layer comprising a pH-sensitive film comprising a pH-sensitive polymer that is insoluble in water at a pH greater than 5; and,
(ii) a matrix comprising a carbomer gelling polymer and sodium bicarbonate, wherein the carbomer gelling polymer and sodium bicarbonate are both present in an amount of about 2 wt % based on the total weight of the dosage form;
wherein the dosage form exhibits an immediate release profile of esketamine having not less than 90% of the esketamine released in 60 minutes, wherein the release profile is evaluated by dissolution of the dosage form in 300 mL of 0.1N HCl media using USP II apparatus at 50 RPM paddle speed and 37° C.;
and,
wherein the dosage form exhibits an immediate release profile of the esketamine when administered to a human in therapeutic doses, and an extended release profile of the esketamine when administered to a human in supratherapeutic doses, or
wherein the dosage form exhibits abuse resistant properties when physically manipulated, or
wherein the dosage form exhibits abuse resistant properties when physically manipulated and administered in a manner not consistent with oral dosing, or
wherein the dosage form exhibits abuse resistant properties when administered in a manner intended to result in administration of the esketamine in a higher than therapeutic dose.

2. The dosage form according to claim 1 , wherein when the dosage form is physically manipulated by crushing to form a population of particles, less than 15% of the population comprises a subpopulation of particles having a particle size of less than 75 μm.

3. The dosage form according to claim 1 , wherein when the dosage form is physically manipulated by crushing to form a population of particles, less than 40 wt. % of the population of particles comprises a subpopulation of particles having a particle size of less than 106 μm, and wherein said subpopulation contains less than 10 wt. % base equivalent of the esketamine of said dosage form.

4. The dosage form according to claim 1 , wherein when the dosage form is physically manipulated by crushing to form a population of particles, less than 35 wt. % comprises a subpopulation of particles having a particle size of 212-500 μm and containing less than 70 wt. % base equivalent of the esketamine of said dosage form.

5. The dosage form according to claim 1 , wherein when the dosage form is physically manipulated by crushing to form a population of particles, less than 30 wt. % comprises a subpopulation of particles having a particle size of 106-212 μm and wherein the subpopulation of particles contains less than 20 wt. % base equivalent of the esketamine of said dosage form.

6. The dosage form according to claim 1 , wherein the dosage form exhibits one or more of the abuse resistant properties when the dosage form is physically manipulated by crushing and subsequent heating prior to the administration in a manner not consistent with oral dosing or in a manner intended to result in administration of the esketamine in a higher than therapeutic dose.

7. The dosage form according to claim 6 , wherein the heating comprises subjecting the physically manipulated dosage form to a temperature of about 200° C.-300° C.

8. The dosage form according to claim 6 , wherein the physically manipulated dosage form is heated for at least one minute.

9. The dosage form according to claim 7 , wherein the heated, physically manipulated dosage form releases less esketamine (base equivalent) after incubation in water or 0.1 N HCl for up to 18 hours, as compared to the release of esketamine from a physically manipulated dosage form control that has not been heated prior to incubation in water or 0.1 N HCl for up to 18 hours.

10. The dosage for according to claim 7 , wherein the heated, physically manipulated dosage form releases at least 20 wt. % less esketamine (base equivalent), as compared to the release of esketamine (base equivalent) from a physically manipulated dosage form control that has not been heated prior to incubation in water or 0.1 N HCl for up to 18 hours.

11. The dosage form according to claim 1 , wherein upon physically manipulating the dosage form by crushing, the physically manipulated dosage form exhibits less than 5 wt. % the esketamine diffusion of powdered pure esketamine or a pharmaceutically acceptable salt thereof, over 60 minutes across a membrane having a molecular weight cutoff of 12-14 kD from a receptor chamber containing a phosphate buffer at pH 6.4 and maintained at 37° C.

12. The dosage form according to claim 1 , wherein upon physically manipulating the dosage form by crushing, the physically manipulated dosage form exhibits less esketamine diffusion across nasal membranes of a human subject when nasally insufflated by the subject, relative to a solution of 140 mg/ml esketamine (base equivalent) in pH 4.5 citrate buffer.

13. The dosage form according to claim 12 , wherein upon physically manipulating the dosage form by crushing, the physically manipulated dosage form exhibits less than 5% the relative esketamine diffusion of a solution of 140 mg/ml esketamine (base equivalent) in pH 4.5 citrate buffer, over 60 minutes across a membrane having a molecular weight cutoff of 12-14 kD from a receptor chamber containing a phosphate buffer at pH 6.4 and maintained at 37° c.

14. The dosage form according to claim 1 , wherein upon physically manipulating the dosage form by crushing, the absorption of esketamine from the physically manipulated dosage form over 60 minutes across a membrane having a molecular weight cutoff of 12-14 kD from a receptor chamber containing a phosphate buffer at pH 6.4 and maintained at 37° C. is less than 20%.

15. The dosage form according to claim 1 , wherein the dosage form further comprises a second population of core-shell particles that do not contain an active pharmaceutical layer.

16. The dosage form according to claim 1 , wherein the cores of the individual core-shell particles of the first population comprise a gelling polymer selected from the group consisting of ethylcellulose, cellulose acetate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, cellulose ether, cellulose ester, cellulose ester ether, cellulose, hydroxypropyl methyl cellulose, hydroxy methyl cellulose, methyl cellulose, hydroxyethylmethyl cellulose, sodium carboxymethyl cellulose, a carbomer polymer, polyethylene oxide, and combinations thereof.

17. The dosage form according to claim 1 , wherein supratherapeutic doses of said dosage form produce a gel in 15 minutes or less, following exposure to an aqueous medium comprising 0.025 N HCl and 70 mM NaCl at 37° C.

18. The dosage form according to claim 17 , wherein when a dual screen apparatus comprising a top screen and a bottom screen is used to extract at least a portion of said gel from said medium, a first quantity of the gel adheres to a lower surface of the top screen of the apparatus and a second quantity of the gel adheres to an upper surface of the bottom screen of the apparatus, wherein the vertical thickness of the second quantity is at least twice

Assignees

• Clexio Biosciences Ltd

Inventors

• Moe Derek
• Seburg Randal
• Rane Sagar

Classifications

• A61K9/5026

  obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates · CPC title

• A61K9/5078

  with drug-free core · CPC title

• A61K9/1676

  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) · CPC title

• A61K31/78

  of acrylic acid or derivatives thereof · CPC title

• A61K31/135 Primary

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title