Abuse-deterrent dosage forms containing esketamine

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.

What is claimed: 
     
         1 . An oral tablet comprising 40 mg of esketamine (base equivalent);
 wherein the total weight of the tablet is of not less than 800 mg;   wherein the esketamine (base equivalent) comprises less than 5.0% by weight of the total weight of the tablet; and   wherein the tablet exhibits an immediate release profile of esketamine having not less than 90% of the esketamine released in 60 minutes, and wherein the release profile is evaluated by dissolution of the tablet in 300 mL of 0.1N HCl media using USP II apparatus at 50 RPM paddle speed and 37° C.   
     
     
         2 . The tablet according to  claim 1 , wherein the tablet 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 tablet exhibits abuse resistant properties when physically manipulated, or wherein the tablet exhibits abuse resistant properties when physically manipulated and administered in a manner not consistent with oral dosing, or   wherein the tablet exhibits abuse resistant properties when administered in a manner intended to result in administration of the esketamine in a higher than therapeutic dose.   
     
     
         3 . The tablet according to  claim 1 , wherein when the tablet 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. 
     
     
         4 . The tablet according to  claim 1 , wherein when the tablet 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 tablet. 
     
     
         5 . The tablet according to  claim 1 , wherein when the tablet 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 tablet. 
     
     
         6 . The tablet according to  claim 1 , wherein when the tablet 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 tablet. 
     
     
         7 . The tablet according to  claim 1 , wherein the tablet exhibits one or more of the abuse resistant properties when the tablet 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. 
     
     
         8 . The tablet according to  claim 7 , wherein the heating comprises subjecting the physically manipulated tablet to a temperature of about 200° C-300° C. 
     
     
         9 . The tablet according to  claim 7 , wherein the physically manipulated tablet is heated for at least one minute. 
     
     
         10 . The tablet according to  claim 7 , wherein the heated, physically manipulated tablet 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 tablet control that has not been heated prior to incubation in water or 0.1 N HCl for up to 18 hours. 
     
     
         11 . The tablet according to  claim 7 , wherein the heated, physically manipulated tablet releases at least 20 wt % less esketamine (base equivalent), as compared to the release of esketamine (base equivalent) from a physically manipulated tablet control that has not been heated prior to incubation in water or 0.1 N HCl for up to 18 hours. 
     
     
         12 . The tablet according to  claim 1 , wherein upon physically manipulating the tablet by crushing, the physically manipulated tablet 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. 
     
     
         13 . The tablet according to  claim 1 , wherein upon physically manipulating the tablet by crushing, the physically manipulated tablet 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. 
     
     
         14 . The tablet according to  claim 13 , wherein upon physically manipulating the tablet by crushing, the physically manipulated tablet 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. 
     
     
         15 . The tablet according to  claim 1 , wherein upon physically manipulating the tablet by crushing, the absorption of esketamine from the physically manipulated tablet 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%. 
     
     
         16 . The tablet according to  claim 1  comprising esketamine HCl. 
     
     
         17 . The tablet according to  claim 1  comprising a total weight of no less than 1000 mg. 
     
     
         18 . An oral tablet for the administration of esketamine to a subject comprising a total weight of not less than 1000 mg, and having 40 mg of esketamine (base equivalent), the esketamine (base equivalent) representing no more than 4.0% by weight of the total weight of the tablet and wherein the tablet exhibits an immediate release profile of esketamine having not less than 90% of the esketamine released in 60 minutes, and wherein the release profile is evaluated by dissolution of the tablet in 300 mL of 0.1N HCl media using USP II apparatus at 50 RPM paddle speed and 37° C. 
     
     
         19 . An oral, immediate release tablet comprising 40 mg esketamine (base equivalent) and wherein the ratio of the percentage by weight of esketamine (base equivalent) of the total weight of the tablet (5%) to the weight of esketamine (base equivalent) (40 mg) is no more than 0.125 to 1. 
     
     
         20 . The tablet of  claim 19 , wherein the ratio is no more than 0.1 to 1.