Abuse-deterrent dosage forms containing esketamine
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.
1. A method of manufacturing an immediate release tablet determined to have no more than about 5 wt. % of 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one comprising
preparing an immediate release tablet comprising between 20 mg and 100 mg of esketamine;
exposing the tablet to a storage period of six months;
after the storage period, measuring by HPLC for the area under a peak corresponding to 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one present in the tablet; and,
determining by HPLC that the total amount of 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one present in the tablet is no more than about 5 wt %;
wherein the peak corresponding to 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one appears at a relative retention time of about 1.3 minutes when using a C18, 100×3.0 mm, 3.51 μm HPLC column at a temperature of 45° C. and a sample temperature of 4° C., with a mobile phase comprising 0.050% TFA in water and 0.0025% TFA in acetonitrile and UV detection rate of 215 nm.
2. The method of claim 1 , wherein the tablet is exposed to 40° C.±2° C. and 75%±5% relative humidity for the six month storage period.
3. The method of claim 1 , wherein the tablet comprises 40-60 mg of esketamine.
4. The method of claim 1 , wherein the tablet comprises 60 mg of esketamine.
5. The method of claim 1 , wherein the tablet further comprises a pH adjuster.
6. The method of claim 5 , wherein the tablet comprises 2 wt %, based on the weight of the tablet, of the pH adjuster.
7. The method of claim 1 , wherein the 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one is measured in an amount of no more than 0.2 wt % after the storage period.
8. The method of claim 1 , wherein the 2-(2-chlorophenyl)-2-(methylamino)-6-methylidenecyclohexan-1-one is measured in a non-detectable amount after the storage period.